Nodding syndrome and doxycycline: promising findings with open questions
Authors: Emmanuel Olal, Ritah Nantale, David Lagoro Kitara
Journal: The Lancet Global Health (2024)

Nodding syndrome is an enigmatic and devastating childhood neurological disorder only found in specific geographic locations in east Africa. This disease is characterised by repeated head nodding for 5–20 nods per minute in children aged 5–15 years at onset.1Gazda S Kitara DL Treatment and rehabilitation outcomes of children affected with nodding syndrome in Northern Uganda: a descriptive case series.Pan Afr Med J. 2018; 29: 228Crossref PubMed Scopus (8) Google Scholar, 2Pollanen MS Onzivua S McKeever PM et al.The spectrum of disease and tau pathology of nodding syndrome in Uganda.Brain. 2023; 146: 954-967Crossref PubMed Scopus (0) Google Scholar The syndrome is clustered with spatial temporality; it is commonly observed in areas with endemic Onchocerca volvulus where family members and relatives have higher burdens than other community members.1Gazda S Kitara DL Treatment and rehabilitation outcomes of children affected with nodding syndrome in Northern Uganda: a descriptive case series.Pan Afr Med J. 2018; 29: 228Crossref PubMed Scopus (8) Google Scholar, 2Pollanen MS Onzivua S McKeever PM et al.The spectrum of disease and tau pathology of nodding syndrome in Uganda.Brain. 2023; 146: 954-967Crossref PubMed Scopus (0) Google Scholar Currently, there is no known cause or universally agreed biomarker for nodding syndrome diagnosis, but rather syndromic or clinical criteria, thus causing considerable mix-up.3Kodja KG Onzivua S Fong A Kim P Lagoro Kitara D Pollanen MS Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus.Biochem Biophys Rep. 2023; 35101498PubMed Google Scholar Several hypotheses on the underlying cause of nodding syndrome have been advanced, including infectious agents, nutritional deficiencies, toxins, and underlying genetic or autoimmune disorders.4Pollanen MS Onzivua S The tau hypothesis of nodding syndrome in Africa.PLoS Negl Trop Dis. 2023; 17e0011526Crossref PubMed Scopus (0) Google Scholar, 5Hotterbeekx A Vieri MK Ramberger M et al.No Evidence for the involvement of leiomodin-1 antibodies in the pathogenesis of onchocerciasis-associated epilepsy.Pathogens. 2021; 10: 845Crossref PubMed Scopus (17) Google Scholar, 6Nanda Vivek Miano Joseph M Leiomodin-1, a new serum response factor-dependent target gene expressed preferentially in differentiated smooth muscle cells.J Biol Chem. 2012; 287: 2459-2467Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar In The Lancet Global Health, Richard Idro and colleagues7Idro 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; (published online May 13.)https://doi.org/10.1016/S2214-109X(24)00102-5PubMed Google Scholar hypothesised that nodding syndrome is a neuroinflammatory disorder induced by antibodies to O volvulus or its Wolbachia symbiont cross-reacting with host neuronal proteins, and that doxycycline can be used for treatment. To our knowledge, the authors offer the first ever evidence of the potential benefits of doxycycline treatment in managing complications associated with nodding syndrome. In a study population of 240 children and adolescents in northern Uganda, the median duration of nodding syndrome symptoms was 9 years (IQR 6–10); 232 (97%) participants had O volvulus, and 157 (65%) had autoantibodies to human neuronal proteins.7Idro 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; (published online May 13.)https://doi.org/10.1016/S2214-109X(24)00102-5PubMed Google Scholar The most common plasma autoantibodies were to protein deglycase (human DJ-1; 85 [35%]) and leiomodin-1 (77 [32%]), and in cerebrospinal fluid, to human DJ-1 (27 [11%]) and leiomodin-1 (14 [6%]). On immunohistochemistry, 46 (19%) participants had cerebrospinal fluid autoantibodies to neuronal proteins, including leiomodin-1 (26 [11%]), GABABR, CASPR2, or unknown targets (28 [12%]). However, 6 weeks of doxycycline treatment had no effect on autoantibodies to human neuronal proteins, seizure control, disease severity, or quality of life.1Gazda S Kitara DL Treatment and rehabilitation outcomes of children affected with nodding syndrome in Northern Uganda: a descriptive case series.Pan Afr Med J. 2018; 29: 228Crossref PubMed Scopus (8) Google Scholar Nevertheless, the authors reported that at 24 months, doxycycline significantly decreased Ov16 antibody concentration signal-to-noise ratios in the doxycycline group compared with the placebo group. In addition, the relative risk of acute seizure-related hospitalisations (0·43 [95% CI 0·20–0·94], p=0·028) and death (0·46 [0·24–0·89], p=0·028) were significantly lower in the doxycycline group.7Idro 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; (published online May 13.)https://doi.org/10.1016/S2214-109X(24)00102-5PubMed Google Scholar O volvulus is endemic in sub-Saharan Africa, Asia, and South America; however, nodding syndrome has been identified and confirmed by WHO exclusively in southern Tanzania, South Sudan, Liberia, and northern Uganda. An endemic disease (O volvulus) causing a clustered disease (nodding syndrome) raises interesting questions and puzzles to solve. A report from the Ugandan Ministry of Health supports the information that the last new case of nodding syndrome in the country was in 2012.8Gumisiriza N Mubiru F Siewe Fodjo JN et al.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.Infect Dis Poverty. 2020; 9: 12Crossref PubMed Scopus (50) Google Scholar According to the Ministry of Health, deworming the population of O volvulus using ivermectin has been ongoing in northern Uganda since early 2000, in addition to aerial spraying of rivers that harbour the black fly that transmits the worm in 2012, and this coincided with reduced or no incidence of nodding syndrome in northern Uganda.8Gumisiriza N Mubiru F Siewe Fodjo JN et al.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.Infect Dis Poverty. 2020; 9: 12Crossref PubMed Scopus (50) Google Scholar The study by Idro and colleagues was conducted 4 years after the last new case of nodding syndrome was observed in the region. Although this was an enlightening study, the fact that all participants had symptoms of nodding syndrome between 6 and 10 years in duration restricted the ability to assess the temporal relationship between O volvulus infection and onset of nodding syndrome. In addition, Idro and colleagues could not definitively confirm the primary hypothesis that neuroinflammation secondary to O volvulus is the sole cause of nodding syndrome, as evidenced by low autoantibodies to protein deglycase in the cerebrospinal fluid of children with nodding syndrome. However, previous studies in Uganda using immunohistochemistry on brains of deceased individuals with nodding syndrome found no evidence of encephalopathy or leiomodin-1, a key factor in the neuroinflammatory theory, except in the intima of blood vessels. This casts doubts on the sole role of neuroinflammation in the aetiology of nodding syndrome.2Pollanen MS Onzivua S McKeever PM et al.The spectrum of disease and tau pathology of nodding syndrome in Uganda.Brain. 2023; 146: 954-967Crossref PubMed Scopus (0) Google Scholar, 3Kodja KG Onzivua S Fong A Kim P Lagoro Kitara D Pollanen MS Nodding syndrome is unlikely to be an autoimmune reaction to leiomodin-1 after infection by Onchocerca volvulus.Biochem Biophys Rep. 2023; 35101498PubMed Google Scholar, 5Hotterbeekx A Vieri MK Ramberger M et al.No Evidence for the involvement of leiomodin-1 antibodies in the pathogenesis of onchocerciasis-associated epilepsy.Pathogens. 2021; 10: 845Crossref PubMed Scopus (17) Google Scholar, 6Nanda Vivek Miano Joseph M Leiomodin-1, a new serum response factor-dependent target gene expressed preferentially in differentiated smooth muscle cells.J Biol Chem. 2012; 287: 2459-2467Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Furthermore, although the observed O volvulus antibody levels and human neuronal proteins among participants provide valuable insights, the absence of baseline data on O volvulus antibody levels in healthy children restricts the generalisability of these findings. There is also a possibility that O volvulus infection occurs together with other underlying conditions, such as malaria and upper respiratory tract infections,9Vieri MK Hendy A Mokili JL Colebunders R Nodding syndrome research revisited.Int J Infect Dis. 2021; 104: 739-741Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar and the febrile illness-free period offered by doxycycline treatment among the intervention group could partly explain the observed findings. Despite these limitations, the study by Idro and colleagues paves the way for future research on the role of doxycycline as an adjunct treatment for nodding syndrome and other seizure disorders, and promotes further investigation into the specific mechanisms through which O volvulus contributes to nodding syndrome.9Vieri MK Hendy A Mokili JL Colebunders R Nodding syndrome research revisited.Int J Infect Dis. 2021; 104: 739-741Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar Future studies on the causes of nodding syndrome need to prioritise dietary excitatory amino acids10Miyauchi Y Shiraishi A Abe K Sato Y Kita K Excitatory amino acids, possible causative agents of nodding syndrome in eastern Africa.Trop Med Health. 2023; 51: 30Crossref PubMed Scopus (0) Google Scholar and dietary neurotoxins in malnourished children during famine2Pollanen MS Onzivua S McKeever PM et al.The spectrum of disease and tau pathology of nodding syndrome in Uganda.Brain. 2023; 146: 954-967Crossref PubMed Scopus (0) Google Scholar as potential risk factors or causes of nodding syndrome. We declare no competing interests. Doxycycline for the treatment of nodding syndrome: a randomised, placebo-controlled, phase 2 trialNodding syndrome is strongly associated with O volvulus and the pathogenesis is probably mediated through an O volvulus induced autoantibody response to multiple proteins. Although it did not reverse disease symptoms, doxycycline or another prophylactic antibiotic could be considered as adjunct therapy to antiseizure medication, as it might reduce fatal complications from acute seizures and status epilepticus induced by febrile infections. Full-Text PDF Open Access