By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN
SYNOPSIS: Nodding syndrome is a form of pediatric encephalopathy with epilepsy that is associated with Onchocerca volvulus infection in children in Africa. While the pathogenesis is not known, doxycycline helps reduce severe seizures and death in children with nodding syndrome.
SOURCE: Idro R, Ogwang R, Anguzu R, et al. Doxycycline for the treatment of nodding syndrome: A randomised, placebo-controlled, phase 2 trial. Lancet Glob Health 2024;12:e1149-e1158.
Nodding syndrome is a progressive encephalopathy with epilepsy that is associated with onchocerciasis and affects about 10,000 children and adolescents in Africa. The seizures seem to be triggered by eating and by exposure to wind or cold air; episodes consist of repetitive bouts of neck atonia with downward head-nodding. Generalized epilepsy also can develop. This disorder was first reported in Tanzania about 60 years ago and has since been reported mostly in Uganda and South Sudan but also in Central African Republic, Democratic Republic of Congo, and Cameroon. Progressive encephalopathy leads to malnutrition, and the ultimate outcome often is death.
The cause of this epileptic encephalopathy is incompletely understood, and most etiologic testing has been unrevealing. Nonetheless, there are clear epidemiologic associations between nodding syndrome and infection by Onchocerca volvulus, the causative agent of river blindness. However, necropsies of affected patients have not revealed parasites in the brain parenchyma.
Some other epilepsy syndromes have autoimmune causes, and pathogenic autoantibodies have been found in the blood and cerebrospinal fluid of patients with nodding syndrome, specifically antibodies to neuronal protein leiomodin 1 and to protein deglycase. Treatment of patients with nodding syndrome usually includes ivermectin (to kill microfilariae of O. volvulus), anti-epileptic medications, and psychiatric therapy. There is no effective medical treatment for adult Onchocerca, and these parasites can live for a decade and a half in subcutaneous nodules.
O. volvulus, like some other filarial parasites, often is infected by the gram-negative bacterial symbiont Wolbachia. Doxycycline can kill Wolbachia and, thus, lead to premature death of (and reduced microfilarial production by) Onchocerca. (Anti-Wolbachia therapy reduces the lifespan of Onchocerca from 10-15 years to nine to 24 months.) Knowing that nodding syndrome is linked to Onchocerca and that the longevity of Onchocerca is linked to its ongoing relationship with Wolbachia, Idro and colleagues postulated that reducing microfilarial production might reduce the formation of autoantibodies that could be responsible for some of the findings of nodding syndrome. The investigators conducted a randomized clinical trial of doxycycline (100 mg orally each day for six weeks) vs. placebo. The researchers wanted to determine if there was any alteration in either the levels of neuronal antibodies two years later or the severity of seizures and the overall disease.
In northern Uganda, 240 patients aged 8-18 years with clinical diagnoses of nodding syndrome based on World Health Organization criteria and with symptoms of nodding syndrome for six to 10 years were included in the study; all children received similar anticonvulsant therapy.
At baseline, 65% of study participants had a relevant neuronal autoantibody in plasma and/or cerebrospinal fluid. Treatment with doxycycline did not change the proportion of children with relevant neuronal antibodies two years into the study. (However, doxycycline treatment did lead to reduced levels of onchocercal antibodies.)
With doxycycline treatment, body mass index improved, as compared to placebo-treated children. Bacterial and malarial infections were less common in doxycycline-treated children than in placebo-treated children.
Fewer doxycycline-treated children than placebo-treated children were hospitalized during the two years of the study due to seizure exacerbations (7% vs. 17%, P = 0.028). Seizure-related deaths occurred in 3% of doxycycline-treated children and in 8% of placebo-treated children (P = 0.028). Overall, about 45% of children achieved freedom from seizures, with no statistically significant difference between treatment groups.
Based on these findings, the authors hypothesized that nodding syndrome is an autoimmune condition resulting from anti-Onchocerca and/or anti-Wolbachia antibodies cross-reacting with neuronal proteins. By depleting Wolbachia, they suggest, doxycycline has the secondary effect of causing early onchocercal death and, thus, reducing the severity of the seizures of nodding syndrome. However, doxycycline treatment was not associated with an overall reduction in nodding syndrome symptoms. Thus, the authors acknowledged that their data conclusively demonstrate neither a favorable direct effect of antimicrobial therapy on the progression of nodding syndrome disease nor proof of the underlying pathophysiology of nodding syndrome.
COMMENTARY
Nodding syndrome continues to be puzzling. The association with onchocerciasis is proven, but the nature of that association is unclear. Twice-yearly ivermectin has reduced the incidence of onchocerciasis in northern Uganda to essentially zero during the past nine years. However, nodding syndrome only occurs in some but not all of the areas where onchocerciasis is common. Also, nodding syndrome is limited to onset during the pediatric and adolescent age range. The pathophysiology of nodding syndrome remains uncertain.
Other parasites also are common in areas where nodding syndrome occurs, but the association is stronger between onchocerciasis and nodding syndrome than between other parasites and nodding syndrome.1,2 Realization that Onchocerca is not found in cerebrospinal fluid or brain autopsy samples suggests that an autoimmune mechanism, rather than a direct central nervous system infection, could lead to nodding syndrome (and to other forms of onchocerciasis-associated epilepsy that affect hundreds of thousands of patients).2,3 Conversely, it is possible that earlier microfilarial invasion of the brain, after which the microfilaria are destroyed, could trigger brain changes leading to nodding syndrome.4 Alternatively, Onchocerca could trigger some other sort of inflammatory reaction in the brain, perhaps involving tau deposits.4
Since Onchocerca and Wolbachia interact symbiotically, treatment of Wolbachia with doxycycline can have the secondary effect of prompting the death of adult forms of Onchocerca.5 It is unlikely that doxycycline has a direct effect on Onchocerca parasites. However, it also is possible that doxycycline treatment led primarily to reductions in bacterial and malarial infections, with the secondary effect of improved nutrition and better host defenses against deterioration with nodding syndrome. Thus, while doxycycline had a favorable effect on children, it is not clear that it really had a significant direct anti-parasitic effect.
These new data from northern Uganda also serve as a reminder to treat not only the infections but also the children harboring the infections. Similarly, new data from Zambia and Malawi demonstrate that outcomes of acute cerebral malaria infection (specifically severe seizures) are improved by aggressive use of acetaminophen and ibuprofen to control fevers.6
References
- Vieri MK, Mandro M, Cardellino CS, et al. Potential parasitic causes of epilepsy in an onchocerciasis endemic area in the Ituri Province, Democratic Republic of Congo. Pathogens 2021;10:359.
- Hotterbeekx A, Van Hees S, Siewe Fodjo JN, Colebunders R. From nodding syndrome to onchocerciasis-associated epilepsy. Rev Neurol (Paris) 2020;176:405-406.
- Hotterbeekx A, Raimon S, Abd-Elfarag G, et al. Onchocerca volvulus is not detected in the cerebrospinal fluid of persons with onchocerciasis-associated epilepsy. Int J Infect Dis 2020;91:119-123.
- Colebunders R, Hadermann A, Siewe Fodjo JN. The onchocerciasis hypothesis of nodding syndrome. PLoS Negl Trop Dis 2023;17:e0011523.
- Ehrens A, Hoerauf A, Hübner MP. Current perspective of new anti-Wolbachial and direct-acting macrofilaricidal drugs as treatment strategies for human filariasis. GMS Infect Dis 2022;10:Doc02.
- Birbeck GL, Seydel KB, Mwanza S, et al. Acetaminophen and ibuprofen in pediatric central nervous system malaria: A randomized clinical trial. JAMA Neurol 2024;Jun 10:e241677. doi: 10.1001/jamaneurol.2024.1677. [Online ahead of print].
