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.

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.

Long-term clinical course and treatment outcomes of individuals with Nodding Syndrome.

Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or controversial. The objectives of this study were to describe the long-term clinical course and treatment outcomes of individuals suffering from Nodding Syndrome. In addition, we aimed to provide a comprehensive characterization of the epileptological and social features of patients with Nodding Syndrome. From 11/2014 to 4/2015, we conducted a hospital-based, cross-sectional and observational study in Mahenge, Tanzania. Seventy-eight individuals (female:male ratio: 40:38, age at examination: 21.1 ± 6.39 (SD) years) have been enrolled, of whom 38 (49%) had also been examined in 2005 and in 2009. The 10-year clinical course analysis of this revisited subgroup revealed a calculated case fatality of 0.8-2.3%. Progressive physical or cognitive deterioration has not been observed in any of the 78 individuals and more than half of the people studied (38/69; 55%) managed to live and work independently. 14/78 individuals (18%) were seizure-free, (no head nodding, no other seizure types), 13 of whom were taking antiseizure medication. Phenytoin was more effective against head nodding seizures (14/19 (74%)) than monotherapy with other available antiseizure medication (phenobarbitone 12/25 (48%) and carbamazepine 7/22 (32%), p = 0.02, chi-square test). Our ten-year clinical outcome data show that Nodding Syndrome is not a fatal disease, however, the response to treatment is worse than in epilepsy patients in general. Phenytoin may be more effective than carbamazepine and phenobarbitone, but further studies are needed to confirm this observation.

Epilepsy and nodding syndrome in association with an Onchocerca volvulus infection drive distinct immune profile patterns.

Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological link is still missing. Cases are found in different African countries (Tanzania, South Sudan, Uganda, Democratic Republic of the Congo, Central African Republic and Cameroon). In our study we investigated immunological parameters (cytokine, chemokine, immunoglobulin levels) in individuals from the Mahenge area, Tanzania, presenting with either epilepsy or nodding syndrome with or without O. volvulus infection and compared them to O. volvulus negative individuals from the same endemic area lacking neurological disorders. Additionally, cell differentiation was performed using blood smears and systemic levels of neurodegeneration markers, leiomodin-1 and N-acetyltyramine-O, ß-glucuronide (NATOG) were determined. Our findings revealed that cytokines, most chemokines and neurodegeneration markers were comparable between both groups presenting with epilepsy or nodding syndrome. However, we observed elevated eosinophil percentages within the O. volvulus positive epilepsy/nodding syndrome patients accompanied with increased eosinophilic cationic protein (ECP) and antigen-specific IgG levels in comparison to those without an O. volvulus infection. Furthermore, highest levels of NATOG were found in O. volvulus positive nodding syndrome patients. These findings highlight that the detection of distinct biomarkers might be useful for a differential diagnosis of epilepsy and nodding syndrome in O. volvulus endemic areas. Trial-registration: NCT03653975.

Effect of onchocerciasis elimination measures on the incidence of epilepsy in Maridi, South Sudan: a 3-year longitudinal, prospective, population-based study.

BACKGROUND: High onchocerciasis transmission predisposes endemic communities to a high epilepsy burden. The 4·4% epilepsy prevalence documented in 2018 in Maridi, South Sudan, prompted the strengthening of onchocerciasis elimination measures. Community-directed treatment with ivermectin was implemented annually in 2017, 2018, and 2019, interrupted in 2020, and re-implemented biannually in 2021. We aimed to assess the effect of these interventions, along with slash and clear vector control on the incidence of epilepsy, including nodding syndrome. METHODS: In this longitudinal, prospective, population-based study, we did a two-stage house-to-house epilepsy survey before (May 10-30, 2018) and after (March 9-19, 2022) the strengthening of onchocerciasis elimination interventions in South Sudan. Strengthening also included the implementation of a community-based slash and clear vector control method that we initiated in 2019 at the Maridi dam (the main blackfly breeding site). Eight sites were surveyed near the Maridi dam and inclusion required residence in one of these sites. All household residents were first screened by community workers, followed by confirmation of the epilepsy diagnosis by trained clinicians. The primary outcome was epilepsy incidence, including nodding syndrome, which was assessed via self-reported new-onset epilepsy in the previous 4 years of each survey, confirmed by clinician assessment. FINDINGS: The preintervention survey included 17 652 people of whom 736 had epilepsy (315 female and 421 male), and the post-intervention survey included 14 402 people of whom 586 had epilepsy (275 female and 311 male). When biannual community-directed treatment with ivermectin was initiated in 2021, the intervention's coverage rose by 15·7% (95% CI 14·6-16·8); although only 56·6% of the population took ivermectin in 2021. Between 2018 and 2022, epilepsy incidence decreased from 348·8 (307·2-395·8) to 41·7 (22·6-75·0) per 100 000 person-years. Similarly, the incidence of nodding syndrome decreased from 154·7 (127·6-187·3) to 10·4 (2·7-33·2) per 100 000 person-years. The identified risk factors for epilepsy were: living closer to the Maridi dam, being aged between 6 and 40 years, not taking ivermectin, and being male. INTERPRETATION: In onchocerciasis-endemic areas with high epilepsy prevalence, strengthening onchocerciasis elimination interventions can decrease the incidence of epilepsy, including nodding syndrome. Additional efforts are needed to increase community-directed treatment with ivermectin coverage and sustain blackfly control in Maridi. FUNDING: Research for Health in Humanitarian Crisis, European Research Council, Research Foundation-Flanders, Research Foundation-Flanders, the Italian Agency for Development Cooperation, and La Caixa Foundation.

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.

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.

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.

The spectrum of disease and tau pathology of nodding syndrome in Uganda.

Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures and death after several years. The most recent outbreak of nodding syndrome occurred in northern Uganda. We now describe the clinicopathologic spectrum of nodding syndrome in northern Uganda. The neuropathologic findings of 16 children or young adults with fatal nodding syndrome were correlated with the onset, duration and progression of their neurological illness. The affected individuals ranged in age from 14 to 25 years at the time of death with a duration of illness ranging from 6-15 years. All 16 cases had chronic seizures. In 10 cases, detailed clinical histories were available and showed that three individuals had a clinical course that was predominantly characterized by epilepsy, whereas the other seven individuals had progressive cognitive, behavioural and motor decline, in addition to epilepsy. The main neuropathologic findings included: tau pathology (16/16 cases), cerebellar degeneration (11/16 cases) and white matter degeneration (7/16 cases). The tau pathology was characterized by filamentous tau-positive deposits in the form of neurofibrillary tangles, pre-tangles and dot-like grains and threads in the neuropil. All cases showed some degree of tau pathology in the neocortex and in the locus coeruleus with frequent involvement of the substantia nigra and tegmental nuclei and lesser involvement of other grey matter sites, but there was a lack of glial tau pathology. The tau pathology in the neocortex showed a multifocal superficial laminar pattern. We conclude that nodding syndrome is a clinicopathological entity associated consistently with tau pathology, but our observations did not establish the cause of the disease, or an explanation for the tau pathology.

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.

Impact of COVID-19 on the well-being of children with epilepsy including nodding syndrome in Uganda: A qualitative study.

OBJECTIVE: To investigate the impact of the COVID-19 pandemic and related restrictions on the access and use of health services by children with epilepsy including nodding syndrome in Uganda. METHODS: Four focus group discussions (FGD) with parents/caregivers of children with epilepsy and five in-depth interviews with key informants were conducted between April and May 2021 at Butabika National Mental Referral Hospital and Kitgum General Hospital. RESULTS: COVID-19-related restrictions, including the halting of non-essential services and activities, and suspension of public transport, created several challenges not only for children with epilepsy and their parents/caregivers but also for their healthcare providers. Study participants described extreme transport restrictions that reduced their access to healthcare care services, increased food insecurity and shortage or inability to afford essential medicines as consequences of COVID-19-related restrictions. However, parents/caregivers and healthcare workers adopted several coping strategies for these challenges. Parents/caregivers mentioned taking on casual work to earn an income to buy food, medicines, and other necessities. Healthcare workers intensified outreach services to affected communities. A positive impact of lockdown measures described by some FGD participants was that most family members stayed at home and were able to care for children with epilepsy in turn. CONCLUSIONS: Our study highlights the significant negative impact of the COVID-19 pandemic and related restrictions on access to health services and the general well-being of children with epilepsy. Decentralized epilepsy treatment services and nutritional support could reduce the suffering of children with epilepsy and their families during the ongoing COVID-19 pandemic and similar future emergencies.

Epidemiology of nodding syndrome in the Greater Mundri area, South Sudan: Prevalence, spatial pattern and environmental risk factors.

BACKGROUND: Nodding syndrome (NS) is a progressive neurological disease that has been described in several sub-Saharan African counties, but South Sudan is considered the most affected. However, knowledge about the exact burden and the epidemiological risk factors of NS in South Sudan is lacking. OBJECTIVE: To determine the prevalence, distribution and epidemiological risk factors of NS in the Greater Mundri area, the epicenter of NS in South Sudan. METHODS: A NS prevalence house-to-house survey was conducted in multiple villages between February 2018 and November 2019. Geographical distribution and clustering of NS cases was identified using spatial and binomial regression analysis. Epidemiological risk factors of NS were identified using univariate and multivariate models. RESULTS: Of the 22,411 persons surveyed in 92 villages, 607 (2.7%) persons with NS were identified, of which 114 (19%) were new-onset cases. The highest prevalence was found in Diko village with a prevalence of 13.7%. NS showed a significant spatial pattern with clustering of cases between adjacent households and along rivers. Risks factors for NS include all behaviors around rivers (drinking, cooking, handwashing and bathing) and exposure to poultry. On the other hand, ownership of mobile phone decreased the risk of NS. Many other factors, including prior ivermectin treatment and internal displacement were not associated with NS. CONCLUSION: Our study demonstrates a very high burden of the NS disease in the Greater Mundri area, strengthens the association with rivers, and identified possible new clues for an underlying cause.

'There Were Moments We Wished She Could Just Die': The Highly Gendered Burden of Nodding Syndrome in Northern Uganda.

Nodding Syndrome (NS) occurs within a wide spectrum of epilepsies seen in onchocerciasis endemic areas of sub-Saharan Africa. It has debilitating consequences on affected individuals and increases the socio-economic, physical and psychological burden on care-givers and their households, diminishing their standing within the community. Social science research on the disproportionate burden of the disease on females is limited. Based on ethnographic research over 3 years in northern Uganda, we explored the burden of being ill and care-giving for persons with NS from a gendered perspective. We found that NS-affected females were at greater risk of physical and psychological abuse, sexual violence, unwanted pregnancies, sexually transmitted infections and stigma, in a context of deteriorating socio-economic conditions. Primary care-givers of the NS-affected, mostly women, struggled to make ends meet and were subjected to stigma and abandonment. Targeted interventions, including legal protection for affected females, stigma reduction, and psycho-social and financial support are needed.

First description of Nodding Syndrome in the Central African Republic.

BACKGROUND: The term Nodding Syndrome (NS) refers to an atypical and severe form of childhood epilepsy characterized by a repetitive head nodding (HN). The disease has been for a long time limited to East Africa, and the cause is still unknown. The objective of this study was to confirm the existence of NS cases in Central African Republic (CAR). METHODOLOGY/PRINCIPAL FINDINGS: This was a cross-sectional descriptive study in the general population. The identification of NS cases was conducted through a door-to-door survey in a village near Bangui along the Ubangui River. Based on Winkler's 2008 and the World Health Organization (WHO)'s 2012 classifications, the confirmation of cases was done by a neurologist who also performed the electroencephalograms. No laboratory tests were done during this investigation. Treatment was offered to all patients. A total of 6,175 individuals was surveyed in 799 households. After reviewing the cases, we identified 5 NS cases in girls aged between 8 and 16. The age of onset of the seizures was between 5 and 12 years of age. Two cases were classified as "HN plus" according to Winkler's 2008 classification. Four NS cases were classified as probable and one as confirmed according to the WHO's 2012 classification. Three of them presented with developmental delay and cognitive decline, and one had an abnormally low height-for-age z-score. Electroencephalographic abnormalities were found in four patients. CONCLUSIONS/SIGNIFICANCE: Nodding Syndrome cases were described in CAR for the first time. Despite certain peculiarities, these cases are similar to those described elsewhere. Given that only a small part of the affected area was investigated, the study area along the Ubangui River needs to be expanded in order to investigate the association between Onchocerca volvulus and NS and also evaluate the real burden of NS in CAR.

Systemic and cerebrospinal fluid immune and complement activation in Ugandan children and adolescents with long-standing nodding syndrome: A case-control study.

OBJECTIVE: Nodding syndrome is a poorly understood epileptic encephalopathy characterized by a unique seizure type-head nodding-and associated with Onchocerca volvulus infection. We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder. METHOD: We conducted a case-control study of 154 children (8 years or older) with long-standing nodding syndrome and 154 healthy age-matched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from hematological malignancy during routine follow-up. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using ELISA or Multiplex Luminex assays. O volvulus infection was assessed by serology for anti-OV-16 IgG levels. RESULTS: The mean (SD) age of the population was 15.1 (SD: 1.9) years, and the mean duration of nodding syndrome from diagnosis to enrollment was 8.3 (SD: 2.7) years. The majority with nodding syndrome had been exposed to O volvulus (147/154 (95.4%)) compared with community children (86/154 (55.8%)), with an OR of 17.04 (95% CI: 7.33, 45.58), P < .001. C5a was elevated in CSF of children with nodding syndrome compared to controls (P < .0001). The levels of other CSF markers tested were comparable between cases and controls after adjusting for multiple comparisons. Children with nodding syndrome had lower plasma levels of IL-10, APRIL, CCL5 (RANTES), CCL2, CXCL13, and MMP-9 compared with community controls (P < .05 for all; multiple comparisons). Plasma CRP was elevated in children with nodding syndrome compared to community children and correlated with disease severity. SIGNIFICANCE: Nodding syndrome is associated with exposure to O. volvulus. Compared to controls, children with long-standing symptoms of nodding syndrome show evidence of complement activation in CSF and altered immune activation in plasma.

Nodding syndrome: bridging the gap-a scoping review protocol.

INTRODUCTION: Nodding syndrome (NS) is an encephalopathy of unknown origin that affects children aged between 3 and 15 years old. Cases have been reported since the 1950 in Tanzania and South Sudan, the most heavily affected population is the Acholi community in Uganda. In response to the high incidence of the disease, the Ugandan Government has developed a management algorithm, but access to such measures in affected communities is limited. There is little funding for research on the disease, consequently, few studies have been conducted to date. Nevertheless, the number of scientific publications on NS has increased since 2013, reporting several aetiological hypotheses, management algorithms and cases of stigmatisation; however, none has obtained conclusive results.This document describes a protocol for a scoping review of NS to date aimed at obtaining a broad overview of the disease. The results will identify gaps in knowledge in order to better guide future research, intervention strategies, health policies in areas at risk and cooperation and development programmes. METHODS AND ANALYSIS: To identify the relevant data, we will conduct a literature search using the electronic databases PubMed/Medline, Embase, Social Science Citation Index Scopus, Scientific Electronic Library Online (SciELO), Literatura Latinoamericana y del Caribe en Ciencias de la Salud (LILACS), Social Science Citation Index Expanded and The Cochrane Library. We will also include grey literature. The search strategy will be designed by a librarian.Two members of the team will work independently to identify studies for inclusion and perform data extraction. The search results will be assessed by two independent reviewers and data from the included studies will be charted and summarised in duplicate. The data will be summarised in tables and figures to present the research landscape and describe and map gaps. ETHICS AND DISSEMINATION: Ethical approval is not required. The scoping review will adhere to the Preferred Reporting Items for Systematic Reviews andMeta-Analyses-ScR guidelines. The results will be disseminated at scientific congresses and meetings.

Economic burden of the persistent morbidity of nodding syndrome on caregivers in affected households in Northern Uganda.

BACKGROUND: Nodding syndrome (NS), is an unexplained form of epilepsy which leads to stunted growth, cognitive decline, and a characteristic nodding of the head. Current data about its impact on households in Uganda is scarce. Therefore, this study aims to assess the economic burden of the persistent morbidity of NS on caregivers in affected households in Northern Uganda. METHODS: A cross-sectional cost-of-care study was conducted from January 2019 to February 2019 in Lakwela village-Northern Uganda in 14 households, who are members of a community-based organization (CBO) established in the village with the support of a Japanese research team, (Uganda-Japan Nodding Syndrome Network). Data was collected through questionnaires. Both direct (medical and non-medical) and indirect (informal care) costs of caregiving were assessed. Indirect costs were valued using the human-capital method as loss of production. RESULTS: Direct costs constituted a higher proportion of costs for NS households, accounting for on average 7.7% of household expenditure. The annual weighted mean cost per NS patient was estimated at 27.6 USD (26.4 USD direct costs, 96.2% and 1.2 USD indirect cost, 3.8%). Average time spent on informal caregiving was 4.4 ±1.7 (standard deviation) hours/week with an estimated annual informal caregiving cost of 24.85 USD and gross domestic product (GDP) loss of 412.40 USD. CONCLUSION: Direct costs due to NS are still high among households in this study. More studies are needed to investigate measures that could help bring down these costs and equally reduce the day-to-day disruption of caregiver's activities; consequently, improving the lives of these affected households and communities.

Prevalence and incidence of nodding syndrome and other forms of epilepsy in onchocerciasis-endemic areas in northern Uganda after the implementation of onchocerciasis control measures.

BACKGROUND: Around 2007, a nodding syndrome (NS) epidemic appeared in onchocerciasis-endemic districts of northern Uganda, where ivermectin mass distribution had never been implemented. This study evaluated the effect of community-directed treatment with ivermectin (CDTI) and ground larviciding of rivers initiated after 2009 and 2012 respectively, on the epidemiology of NS and other forms of epilepsy (OFE) in some districts of northern Uganda. METHODS: In 2012, a population-based community survey of NS/epilepsy was carried out by the Ugandan Ministry of Health in Kitgum and Pader districts. In August 2017, we conducted a new survey in selected villages of these districts and compared our findings with the 2012 data. In addition, two villages in Moyo district (where CDTI was ongoing since 1993) served as comparative onchocerciasis-endemic sites in which larviciding had never been implemented. The comparison between 2012 and 2017 prevalence and cumulative incidence were done using the Fisher's and Pearson's Chi-square tests at 95% level of significance. RESULTS: A total of 2138 individuals in 390 households were interviewed. In the selected villages of Kitgum and Pader, there was no significant decrease in prevalence of NS and OFE between 2012 and 2017. However, the cumulative incidence of all forms of epilepsy decreased from 1165 to 130 per 100 000 persons per year (P = 0.002); that of NS decreased from 490 to 43 per 100 000 persons per year (P = 0.037); and for OFE from 675 to 87 per 100 000 persons per year (P = 0.024). The median age of affected persons (NS and OFE) shifted from 13.5 (IQR: 11.0-15.0) years in 2012 to 18.0 (IQR: 15.0-20.3) years in 2017; P <  0.001. The age-standardized prevalence of OFE in Moyo in 2017 was 4.6%, similar to 4.5% in Kitgum and Pader. CONCLUSIONS: Our findings support the growing evidence of a relationship between infection by Onchocerca volvulus and some types of childhood epilepsy, and suggest that a combination of bi-annual mass distribution of ivermectin and ground larviciding of rivers is an effective strategy to prevent NS and OFE in onchocerciasis-hyperendemic areas.