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Nodding Syndrome: a trans-disciplinary approach to identify the cause and decrease the incidence of river epilepsy

Periodic Reporting for period 4 - NSETHIO (Nodding Syndrome: a trans-disciplinary approach to identify the cause and decrease the incidence of river epilepsy)

Reporting period: 2020-04-01 to 2021-11-30

The problem
Nodding syndrome (NS) is a devastating epileptic syndrome appearing in previously healthy children between the ages of 3 and 18 years. The syndrome is characterized by head-nodding, an atonic seizure, which is often associated with a declining cognitive function, psychiatric problems, stunting growth, and early death. Until recently the cause of the syndrome was unknown. Therefore, no strategy for prevention and cure was possible.
NS was initially reported to occur only in onchocerciasis-endemic regions in Tanzania, Uganda and South Sudan. However, a high prevalence of epilepsy was also observed in an onchocerciasis-endemic region in Cameroon where it was called “river epilepsy”.

Importance for society
NS and river epilepsy are catastrophic for the persons, families and villages affected. Most children with NS and river epilepsy are intellectually disabled and have psychiatric problems. Parents are left desperate and living in fear because some children simply wander off, disappear and die. Children often fall in a fire or drown in the river. In most remote onchocerciasis-endemic regions in Africa, people do not have continuous access to anti-epileptic treatment or basic care for burn wounds. Parents generally are not aware that with medical treatment the health condition of the children may improve. Therefore they may abandon their children with resultant malnourishment and early death. There is a belief in the affected communities that epilepsy-affected people are possessed by evil spirits and hence the entire family may be isolated from society.
As children form the social security of the family in these regions, having one or more affected children has a large impact on the family income and social status. Children with epilepsy with intellectual disability will not be able to provide income for the family nor take care of elderly family members. Children with epilepsy require constant care and supervision. As a consequence, a family member may not be able to go to work because he/she needs to watch the epilepsy affected children. Family income is decreasing because having to care for a sick child. Therefore the economic cost of epilepsy is considerable.

Overall objective
The aim of the NSETHIO project was to identify the cause of NS and river epilepsy and to detect ways to prevent these forms of epilepsy.
We conducted several epilepsy surveys in onchocerciasis-endemic areas, including areas where so far NS had never been reported.
In the Democratic Republic of the Congo (DRC), an epilepsy prevalence between 2 and 6% was documented in many villages near rapid flowing rivers in the Bas Uele, Tshopo and Ituri province. This prevalence is much higher than the median epilepsy prevalence (1.4%) observed in Africa. We discovered that NS is only one of the clinical presentations of “river epilepsy” or onchocerciasis-associated epilepsy (OAE) and that this form of epilepsy is probably present in all onchocerciasis-endemic regions where onchocerciasis is insufficiently controlled. In a clinical trial in Ituri we showed that ivermectin may decrease the frequency of seizures in persons with OAE.
In Cameroon, a high prevalence of OAE was documented in villages in the Mbam and Sanaga valley. Many years of annual community directed distribution with ivermectin (CDTI) reduced the incidence of epilepsy, but insufficiently. In a cohort study a temporal and dose related association was found between the microfilarial load in young children and the development of epilepsy later in childhood.
In Tanzania, a high OAE prevalence was observed in rural villages in the Mahenge area despite, 19 years of CDTI, most likely because of insufficient CDTI coverage.
In northern Uganda we documented that an NS epidemic stopped since bi-annual CDTI and vector control was implemented. Moreover, in a case control study, onchocerciasis and pre-term birth were identified as risk factors for OAE. In western Uganda we showed that OAE dissapeared when onchocerciasis was eliminated in the region.
In South Sudan, surveys in Maridi, Mundri and Mvolo county showed a very high prevalence and incidence of OAE. OAE cases were located close to blackfly breeding sites. In Maridi, a community based "Slach & Clear" intervention at the Maridi dam was found to be very effective in decreasing blackfly biting rates.
In the Central African Republic, in Landja Mboko, an area located about 9 km from the capital city Bangui, where ivermectin was never distributed, a new onchocerciasis transmission zone and cases of NS were detected.
In Nigeria, a survey showed that, thanks to an effective bi-annual CDTI programme, OAE had dissapeared from the Immo valey.

The physiopathology of OAE:
In Uganda a post-mortem study was performed on 9 persons who died of OAE. The cerebellum showed atrophy and loss of Purkinje cells with hyperplasia of the Bergmann glia. Gliosis and features of past ventriculitis and/or meningitis were observed in all except one. Persons who died with NS and other forms of OAE presented similar pathological changes. No O. volvulus microfilariae, nor O. volvulus and Wolbachia DNA were detected in brain samples. Tau deposits were present in certain brains, most likely as a consequence of repetitive uncontrolled seizures.
Cerebrospinal fluid: no microfilaria, nor O. volvulus and Wolbachia DNA were detected
Leiomodine antibodies nor serotonine were found to play a role in the pathogenesis of OAE

Several international workshops, special sessions during conferences, webinars and community meetings about OAE were organized. Our research findings were picked up by several newspapers and disseminated through interviews: e.g. le Monde and BBC world

We developed a policy to prevent and treat OAE for which we obtained an ERCpoc grant. This policy is now implemented in Mahenge, Tanzania and Maridi, South Sudan.
In collaboration with the team of J Souopgui (ULB, Brussels) we developed an OvMANE1 antibody test that together with the OV16 antibody test will increase the sensitivity to detect onchocerciasis antibodies
A link between onchocerciasis and epilepsy was suspected for a long time. However, onchocerciasis was not considered as the cause of NS because NS was believed to occur only in onchocerciasis-endemic regions in Uganda, South Sudan, and Tanzania.
We showed that NS and the Nakalanga syndrome are clinical manifestations of OAE that occur in many onchocerciasis-endemic regions in South Sudan, the DRC, Mahenge in Tanzania, the Mbam valley in Cameroon and the Central African Republic, because of absence or sub-optimal ivermectin coverage. Our studies provide strong epidemiological evidence that O. volvulus is able to trigger the development of epilepsy but we still need to determine the exact pathophysiological mechanism how this may happen. In a moddeling excercise we estimated that 200-400.000 persons may be living in Africa with OAE, a condition that could have been prevented by strengthening onchocerciasis-elimination programmes. Children between the age of 5-15 years, in onchocerciasis-endemic areas with high ongoing transmission, need to receive 6 monthly ivermectin treatment to keep them free of microfilaria during an entire year to protect them to develop epilepsy.
Maridi, South Sudan, house to house survey
Maridi, Boy nodding syndrome since the age of 7 and and blind since the age of 10
DRC, boy with onchocerciasis nodules
R Colebunders during epilepsy prevalence study in Bas Uele province, DRC
NSETHIO participants in Kick-off meeting
"Slash and Clear" community dirrected vector control method
NSETHIO team investigating onchocerciasis associated epilepsy in Ituri, DRC