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Global Health Organization: CDC's Hypothesis of Parasitic Worm causes autoimmune reaction

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Global Health Organization: CDC's Hypothesis of Parasitic Worm causes autoimmune reaction

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This article discusses the CDC's hypothesis of a parasitic worm being the main cause of nodding disease.
Published in 2017

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This is a full case-control study about systemic and cerebrospinal fluid immune and complement activation in Ugandan children

Published in 2020

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Epilepsia Open - 2021 - Ogwang - Systemic and cerebrospinal fluid immune and complement activation in Ugandan children and

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Peer Review Article: Nodding Syndrome: Bridging the gap-a scoping review protocol

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Peer Review Article: Nodding Syndrome: Bridging the gap-a scoping review protocol

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This article walks you through the necessary protocols and policies to be enforced moving forward after learning about NS with the most up to date data.
Published in 2020

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Peer Review Article: Trends in Parasitology

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Peer Review Article: Trends in Parasitology

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This peer-reviewed article holds multiple references and opinions on the disease. It gives insight into causes, effects, and treatment.
Published in 2017

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2023, Biochemistry and Biophysics Reports

Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite Onchocerca volvulus has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of C. elegans (as a proxy for Onchocerca volvulus) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and C. elegans. However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving Onchocerca volvulus and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses.

Relief supplies, including fungicide-treated seed intended for planting but eaten by some because of hunger, were associated with NS in southern Sudan but not in Uganda. Positive and negative associations link prior reports of childhood infection with measles or rubella virus [5,6,11,23], both of which can migrate to the brain where they lay dormant for some years before reactivation in the form of progressive neurodegenerative disease (SSPE or PRP, respectively). Head nodding and neurofibillary degeneration have been reported in measles-related subacute sclerosing pancephalitis (SSPE) [11], a disorder similar to post-rubella panencephalitis (PRP).

Nodding syndrome (NS) is a progressive encephalopathy of children and adolescents characterized by seizures, including periodic vertical head nodding. Epidemic NS, which has affected parts of East Africa, appears to have clinical overlap with sub-Saharan Nakalanga syndrome (NLS), a brain disorder associated with pituitary dwarfism that appears to have a patchy distribution across sub-Sahara. Clinical stages of NS include inattention and blank stares, vertical head nodding, convulsive seizures, multiple impairments, and severe cognitive and motorsystem disability, including features suggesting parkinsonism. Head nodding episodes occur in clusters with an electrographic correlate of diffuse high-amplitude slow waves followed by an electrodecremental pattern with superimposed diffuse fast activity. Brain imaging reveals differing degrees of cerebral cortical and cerebellar atrophy. Brains of NS-affected children with mild frontotemporal cortical atrophy display neurofibrillary pathology and dystrophic neurites immunopositive for tau, consistent with a progressive neurodegenerative disorder. The etiology of NS and NLS appears to be dominated by environmental factors, including malnutrition, displacement, and nematode infection, but the specific cause is unknown.

2018, Trends in Parasitology

There is currently enough evidence that improved onchocerciasis control will lead to a decrease in incidence of OAE [42]. Spencer et al. mentioned that, in their experience, in the Mahenge region in Tanzania, ivermectin did not prevent the emergence of new cases of NS [45]. However, in this region, ivermectin was distributed only once a year, and treatment coverage was never properly assessed.

A high prevalence of epilepsy has been observed in onchocerciasis-endemic regions with high onchocerciasis transmission. Recent epidemiological studies suggest that Onchocerca volvulus infection is the trigger causing the seizures, which appear in previously healthy children between the ages of 3 and 18 years. Persons with onchocerciasis-associated epilepsy present with a wide spectrum of seizures, including atonic and myoclonic neck seizures; but also absences and most frequently generalized tonic-clonic seizures. Often individuals present with intellectual disabilities and psychiatric disorders and occasionally with 'Nakalanga' features such as severe stunting with delayed or absent external signs of sexual development. Onchocerciasis-associated epilepsy, because of its importance as a public health problem, is an additional reason for strengthening onchocerciasis elimination programs.

View all citing articles on Scopus

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Nodding Syndrome in the Spotlight - Placing Recent Findings in Perspective

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Nodding syndrome (NS) is a debated scientific topic. A recently published study suggests that NS is an autoimmune disorder based on findings of cross-...

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This article talks about the many effects Nodding Syndrome has on children at an early age. It is the only post older than 2016. Published in 2012

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Article from the National Institutes of Health. Possible explanation for Nodding Syndrome

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Article from the National Institutes of Health. Possible explanation for Nodding Syndrome

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This article explains a parasitic protein that gets into the brain cells and causes some forms of neurological disorder. Suggesting that this is a true autoimmune disease
Published in 2017

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NIH-funded study also identifies potential new mechanism for some forms of epilepsy.

Researchers at the National Institutes of Health have uncovered new clues to the link between Nodding syndrome, a devastating form of pediatric epilepsy found in specific areas of east Africa, and a parasitic worm that can cause river blindness. The study, published in Science Translational Medicine, suggests that the mysterious neurological disease may be caused by an autoimmune response to the parasitic proteins.

"This study identifies a cause of Nodding syndrome. But more broadly, these findings provide a novel perspective on epilepsy and suggest that some forms of this neurological disorder may be autoimmune in nature," said Avindra Nath, M.D., clinical director of the NIH's National Institute of Neurological Disorders and Stroke (NINDS).

Nodding syndrome is a form of epilepsy that occurs in children between the ages of 5 and 16 who live in distinct regions of Tanzania, Uganda and the Republic of South Sudan. It is characterized by head nodding, seizures, severe cognitive deterioration and stunted growth. Nodding syndrome may lead to malnutrition and patients have died through seizure-associated traumas such as fatal burns and drowning.

Many studies have reported an association between Nodding syndrome and Onchocerca volvulus, a parasitic worm that can also cause river blindness. The worm is spread by black flies in specific geographic areas, where clusters of Nodding syndrome have been observed. However, it was unclear whether the worm caused this neurological disorder.

In this study, Nath and his colleagues compared serum samples from patients with Nodding syndrome and healthy controls who all lived in the same village in Uganda.

The results showed high levels of antibodies to leiomodin-1 in the samples obtained from patients. In addition, antibody to leiomodin-1 was also present in cerebrospinal fluid of patients with Nodding syndrome. Previous studies have shown leiomodin-1 is found in muscles, but this was the first time researchers saw it in the nervous system.

To confirm that finding, Nath's team examined brain tissue and found leiomodin-1 inside brain cells, notably in regions associated with symptoms of Nodding syndrome. Furthermore, when healthy neurons in a dish were treated with serum from the patients and antibodies against leiomodin-1, they did not survive, but removing the antibodies increased brain cell survival.

"These results may ultimately provide a diagnostic test, which can help identify individuals at risk for developing Nodding syndrome," said Tory Johnson, Ph.D., a post-doctoral fellow in Nath's lab who conducted many of the research experiments.

In addition, Nath and his group found that antibodies that bind to leiomodin-1 also attach to proteins from Onchocerca volvulus. Structurally, leiomodin-1 was shown to be very similar to specific proteins from that parasite.

The results of this study suggest that Nodding syndrome may be an autoimmune disease, in which the immune system incorrectly attacks the body's own proteins. According to the researchers, the immune system creates antibodies to fight off the parasite following infection with Onchocerca volvulus. However, those antibodies also bind to leiomodin-1, so the immune system-incorrectly-will attack brain cells that contain that protein, which can result in symptoms of Nodding syndrome.

"The findings also suggest that therapies targeting the immune system may be effective treatments against this disorder and possibly other forms of epilepsy," said Nath. "Another huge implication of this study is that exterminating black flies and getting rid of the parasite should stop the disorder from occurring."

More research is needed to learn about the role of leiomodin-1 in healthy people as well as in individuals with epilepsy. For example, one-third of controls also had leiomodin-1 antibodies, but it is unclear whether these individuals may eventually develop Nodding syndrome.

Nath's team is currently developing an animal model of Nodding syndrome to further study the disease and test potential therapies.

This work was supported by the NIH Intramural Program.

The NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH...Turning Discovery Into Health®
References

Johnson TP et al. Nodding syndrome as an autoimmune reaction to Onchocerca volvulus. Science Translational Medicine. February 15, 2017.

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International study suggests Nodding syndrome caused by response to parasitic protein

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NIH-funded study also identifies potential new mechanism for some forms of epilepsy.

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Dr. Jane Ruth Aceng, minister of health, talks about the association of the black fly that gets into the body of children and the autoimmune reaction.
Published in 2017

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Scientists working on Nodding Syndrome drug

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Amref Health Africa YouTube Video. Neglected Diseases: Nodding Syndrome 

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Amref Health Africa YouTube Video. Neglected Diseases: Nodding Syndrome 

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This video is an intervention about a young girl named Joyce in South-Sudan. She explains her experiences with Nodding Syndrome and how it has effected her and her family. Published in 2022

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Interventions to Curb Nodding Syndrome in South-Sudan

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Case Study by the National Library of Medicine

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Case Study by the National Library of Medicine

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This case study identifies, categorizes, and summarizes the most up-to-date evidence and knowledge gaps regarding Nodding Syndrome.
Published in 2021

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John Frean, Academic Editor

Abstract

Nodding syndrome (NS) is a debilitating yet often neglected neurological disease affecting thousands of children in several sub-Saharan African countries. The cause of NS remains unknown, and effective treatment options are lacking. Moreover, knowledge regarding NS is scarce and is based on a limited number of publications, with no comprehensive overview published to date. Therefore, the aim of this scoping review was to summarise the current evidence and identify existing knowledge gaps in order to help clinicians, scientists, and policymakers develop guidelines for prioritising this severe condition. We searched the Medline (Ovid), Embase (Ovid), Scopus, and Global Health Library databases in accordance with the PRISMA extension for scoping review guidance and in accordance with the Joanna Briggs Institute guidelines and methodology for a scoping review, using keywords describing NS. We then extracted and presented the original data regarding the epidemiology, aetiology, pathophysiology, clinical features, diagnosis, management, and outcomes of NS, as well as community perceptions and the psychosocial and economic impact of NS. Out of 1470 identified articles, a total of 69 were included in this scoping review. Major gaps exist in understanding the aetiology and pathogenesis of NS. Future research is urgently needed not only to address these gaps, but also to study the treatment options, epidemiology, and psychosocial and economic impacts of NS. Innovative interventions and rehabilitation programmes designed to address the psychosocial and economic burdens associated with NS are also urgently needed.

Keywords: nodding syndrome, disease, sub-Saharan Africa

1. Introduction

Nodding syndrome (NS) is a devastating but often neglected neurological condition that affects thousands of individuals in remote and resource-poor regions in several countries throughout sub-Saharan Africa, with major public health, psychosocial, and economic consequences [ 1, 2, 3, 4].

Our current knowledge regarding NS is based on data dispersed among scientific articles, viewpoints, health reports, and case reports; however, no comprehensive systematic review of NS has been published to date. Although a few reviews do exist [ 1, 5, 6], there is a need for an up-to-date and comprehensive summary of the existing evidence. Thus, the aim of this scoping review was to comprehensively identify, categorise, and summarise the most up-to-date evidence and knowledge gaps regarding NS in order to help clinicians, scientists, and policymakers prioritise this severe yet neglected disease.

2. Methods

We performed a scoping review covering the following six domains: (1) epidemiology of NS; (2) aetiology of NS; (3) pathophysiology of NS; (4) clinical features of NS; (5) diagnosis, treatment, and outcomes of NS; and (6) community perceptions and the psychosocial and economic impact of NS. The study was performed in accordance with the PRISMA extension guidelines, as well as guidelines and methods established by the Joanna Briggs Institute for a scoping review as reported by Arksey and O'Malley [ 7, 8] and Levac et al. [ 7, 8].

2.1. Inclusion and Exclusion Criteria

Because no clinical definition of NS existed prior to 2012, we included all studies that reported persons with characteristic head-nodding seizures that currently fit the definition of NS, regardless of the individual's age, country, or year of publication ( Table 1 ). Studies that included epilepsy or onchocerciasis-associated epilepsy (OAE) describing NS patients as a subset were also included if the data regarding the NS subgroup were presented separately. Studies that exclusively described persons with diagnosed epilepsy of non-NS origin and/or other known neurodegenerative diseases were excluded.

Table 1

Inclusion Criteria

Exclusion Criteria

Study design and population

All study designs of persons with nodding syndrome (according to clinical case definition [ 9] or cases with features of nodding syndrome) of any age

Studies of known epilepsies other than NS and other known neurodegenerative diseases

Publications

All publications: Commentaries, editorials, letters, books, book chapters, dissertations, and conference proceedings with primary/original study data

Studies with nonprimary data

Outcome

Epidemiology, aetiology, pathophysiology, clinical features, diagnosis, and treatment of NS; community perceptions and the socioeconomic impact of NS

Language, year, and country

English publications from 1946 onward, from any country

2.2. Systematic Identification of Relevant Studies

We systematically searched the Medline (Ovid), Embase (Ovid), Scopus, and Global Health Library databases for articles published from January 1946 to November 2021 ( Table 2 ). We also identified previously unidentified and/or ongoing studies by searching Google Scholar, the study inventories of the World Health Organization, and the US Centres for Disease Control and Prevention (CDC) website. Additional publications were identified using the 'snowballing' method (i.e., searching the reference lists in all included studies).

Table 2

Database

Search Terms

Embase

#1. 'nodding syndrome'/exp
#2. (nodding NEAR/2 (head OR disease OR syndrome)):ti,ab,kw
#3. river epilepsy':ti,ab,kw
#4. onchocerciasis'/exp OR 'onchocerca'/exp OR onchocerc *:ti,ab,kw
#5. epilepsy'/exp OR nodding:ti,ab,kw OR epilepsy *:ti,ab,kw OR seizure *:ti,ab,kw
#6. #4 AND #5
#7. #1 OR #2 OR #3 OR #6

Medline

#1. exp Nodding Syndrome/
#2. (nodding adj2 (head or disease or syndrome)).ti,ab,kf.
#3. river epilepsy.ti,ab,kf.
#4. exp Onchocerciasis/or exp Onchocerca/or onchocerc *.ti,ab,kf.
#5. exp Epilepsy/or (nodding or epilepsy * or seizure *).ti,ab,kf.
#6. 4 and 5
#7. 1 or 2 or 3 or 6

Scopus

TITLE-ABS-KEY ((nodding AND near/2 (head OR disease OR syndrome)) OR 'river AND epilepsy' OR (onchocerc* AND (nodding OR epileps* OR seizure*)))

Global Health Library

ab:(nodding AND (disease OR syndrome OR head) OR 'river epilepsy' OR (onchocerc * and (nodding or epilepsy * or seizure *)))
ti:((nodding AND (disease OR syndrome OR head) OR 'river epilepsy' OR (onchocerc * and (nodding or epilepsy * or seizure *))))

2.3. Selection of Relevant Studies, Data Extraction, and Reporting of Results

After removing duplicate records, authors GA and AE screened the titles and abstracts of all retrieved articles, excluded any that did not satisfy the inclusion and exclusion criteria, and then performed a full-text screen of the remaining articles. Any disagreements between GA and AE were resolved through discussion with all authors. GA then extracted the data into predefined outcome tables for each of the six outcomes, and AE reviewed 20% of the extracted data (selected at random) for accuracy. Statistical values such as odds ratios and p-values were not recalculated. The results were then summarised in tables and figures where possible, and a narrative synthesis was used to describe all other findings.

3. Results

The initial literature search identified a total of 1470 published articles. After duplicate records were removed, 1036 articles remained, 833 of which were excluded after screening the title and/or abstract. After full-text screening of the remaining 203 articles and adding one additional study based on screening the references, a total of 69 articles met the inclusion criteria and were included in our review ( Figure 1 and Figure 2 ).

3.1. Epidemiology

Twenty-two studies in our dataset reported on the epidemiology of NS. The first reports of NS cases came from southern Tanzania between the 1930s and the 1960s [ 10]. These early reports were followed decades later by reports from Liberia [ 11], southern Sudan (now officially known as the Republic of South Sudan) [ 3, 12], western Uganda [ 13], and northern Uganda [ 14] ( Figure 3 ). Recently, NS was reported in regions within the Democratic Republic of Congo (DRC) [ 15], Cameroon, and the Central African Republic [ 16, 17] ( Figure 3 ).

On a regional level, the overall prevalence of NS was reported to be 4.6%, 0.7%, 0.4%, and 0.3% for South Sudan (Western Equatoria) [ 3, 18], northern Uganda (Kitgum, Pader, and Lamwu districts) [ 19], the DRC (town of Aketi) [ 20], and Tanzania (Ulang district and Morogoro region) [ 21], respectively. In Cameroon (Bilomo, Kelleng, Ngongol, Nyamongo, and Bayomen), the reported prevalence of NS among a subgroup of patients with epilepsy was 21.8% [ 16]. Finally, in the Central African Republic, a total of five cases were identified among 6175 individuals [ 17].

In villages, NS has been reported to cluster around rapidly flowing rivers infested with blackflies ( Simulium spp.) [ 12, 15, 16, 18, 20, 22, 23, 24, 25] and in families, with some families having two or more affected members [ 3, 10, 19, 26, 27, 28, 29]. In addition, NS has also been associated with poverty, food shortage, and a history of displacement [ 12, 18, 23, 25].

3.2. Aetiology

The aetiology of NS was investigated and reported by 18 studies in our dataset, which were further subdivided into the following seven categories (with some studies reporting more than one category): infections ( n = 11), nutritional deficiencies ( n = 4), toxins ( n = 5), and autoimmune ( n = 4), hormonal ( n = 3), metabolic ( n = 2), and genetic factors ( n = 1). These categories are discussed in detail below.

3.2.1. Infection

With respect to parasitic infection, most studies focused on Onchocerca volvulus (OV) infection ( Table 3 ) and studied the association between NS and OV infection using skin snip microscopy, serology (Ov16 IgG detection using ELISA and OvFAR/MSA detection using the luciferase immunoprecipitation system), and PCR analysis. We found that four case-control studies using skin snip microscopy measured a significantly higher prevalence of OV infection in NS cases (range: 71.1-96.7%) compared to controls (range: 43.7-53.9%) [ 12, 18, 30, 31]. In addition, one case study using skin snip microscopy found a higher density of OV microfilaria in NS cases compared to patients with other forms of epilepsy [ 32]. In contrast, case studies using PCR on cerebrospinal fluid (CSF) samples did not detect either genomic material of OV in 139 cases [ 12, 29, 33, 34] or species of Wolbachia (an endosymbiotic bacteria that occurs together with OV) in CSF samples taken from 10 NS cases [ 33]. In addition, Mansonella perstans infection, which was detected using microscopy on blood samples, was significantly associated with NS in one case-control study, with an odds ratio (OR) of 3.2 ( p = 0.005) [ 12] ( Table 3 ). Finally, we found no association between NS and the presence of any other parasitic infections, including Loa loa, Wuchereria bancrofti, Trypanosoma gambiense (a protozoan that causes human African trypanosomiasis, or sleeping sickness), and Taenia solium (an intestinal tapeworm that causes cysticercosis) [ 12, 31].

Table 3

Pathogen

Location

Test

Cases

Controls

Odds Ratio (95% CI)

p-Value

Reference

Country

Area (Year)

N

%

N

%

Onchocerca volvulus

South Sudan

Lui (2001)

SSM

39

89.7

31

48.3

9.2 (2.7-3.26)

0.00003

[ 12, 18]

Lui (2002)

SSM

13

92.3

16

43.7

15.4 (1.6-148.8)

0.008

[ 12, 18]

Ov16 IgG

39

66.7

44

31.8

3.14 (1.08-9.13)

-

OvFAR/MSA

39

94.9

41

48.8

14.4 (2.65-78.3)

Amadi (2001)

BM

30

66.6

34

50

Amadi (2001)

30

0

34

7.6

-

Amadi (2001)

30

0

34

5.8

PCR

16

0

0

-

-

-

IgG

38

26.3

30

33.3

0.81 (0.24-2.75)

-

With respect to viruses, three case-control studies investigated measles infection using a previous history of measles infection as reported by the parents or legal guardians, with conflicting results ( Table 3 ). The first study (conducted in South Sudan in 2002) reported an inverse association between prior measles infection and NS (OR: 0.13; p = 0.025) [ 12]. The second study (conducted in Uganda in 2009) found no significant association (OR: 3.3; 95% CI: 0.8-13.6) [ 31], and the third study (also conducted in Uganda, but in 2014) found a significant positive association between measles infection and NS (OR: 6; p = 0.047) [ 35]. In addition, no association was identified between hepatitis E infection and NS [ 31]. Finally, a recent case-control study found no association between NS and known viruses including Anneloviridae, Hepadnaviridae (hepatitis B), Flaviviridae, Herpesviridae, Polyomaviridae (human polyomavirus), Papillomaviridae, and Virgaviridae [ 36].

Our search revealed no studies regarding bacterial infections. Finally, there was no association between prion disease and NS (based on a reported history of eating monkey meat) [ 31].

3.2.2. Nutritional Deficiency

A case-control study in Uganda found that compared to controls, NS cases had lower plasma levels of vitamin B6 (OR: 7.2; p = 0.001) and higher plasma 3-hydroxykynurenine levels (OR: 4.50; p = 0.013) [ 38] ( Table 4 ). In contrast, however, three other studies conducted in Uganda and Tanzania found no such associations [ 31, 39, 40].

Table 4

Micronutrient

Location

Cases

Controls

Odds Ratio (95% CI)

p-Value

Reference

Country

Area (Year)

N

%

N

%

No significant association was found between NS and other micronutrient deficiencies, including vitamin A, vitamin B12, folate, zinc, and selenium [ 31].

3.2.3. Toxins

With respect to food-related toxins, a history of consuming maize (OR: 4.0; p = 0.05), mouldy maize (OR: 4.3; p = 0.009) [ 35], relief foods (OR: 4.0; p = 0.02) [ 35, 38], and either red or brown sorghum (OR: 6.22; p = 0.05) [ 12] was significantly associated with NS ( Table 5 ). One study also investigated the possible underlying aetiology associated with consuming mouldy foods by examining the presence of various mycotoxins (aflatoxin, ochratoxin, and ribotoxin deoxynivalenol) present in contaminated foods (maize, sorghum, millet, and groundnuts), but found no association [ 41].

Table 5

Toxins

Location

Test

Cases

Controls

Odds Ratio (95% CI)

p-Value

Reference

Country

Area (Year)

N

%

N

%

Another case-control study failed to confirm the association between red/brown sorghum and NS [ 31]. Interestingly, one study reported an association-albeit not significant-between NS and a history of eating baboon meat [ 18], whereas other studies found no association between NS and the consumption of agricultural seeds, cassava, river fish, insects, rodent meat, or bush meat (including brains) [ 12, 31]. Finally, one case-control study detected the mycotoxins α-zearalenone, aflatoxin M1, and T-2 toxin in the urine of both cases and controls, but found no significant difference between cases and controls [ 42].

Aside from food-related toxins, one study in Uganda found a positive association between NS and the use of crushed plant roots as traditional medicines (OR: 5.4; 95% CI: 1.3-22.1) [ 31] ( Table 5 ). However, another study conducted in the same area found no such association (OR: 1.29; 95% CI: 0.47-3.6) [ 35]. Exposure to toxins from war munitions was associated with NS in Uganda (OR: 13.9; 95% CI: 1.4-135) [ 31], but not in South Sudan [ 12, 30]. Finally, no association was found between NS and exposure to copper or mercury and the source of water for domestic use (river, borehole, spring, shallow well, or pipe) [ 31].

3.2.4. Autoimmunity

One case-control study used a protein array to screen for a large number of autoantibodies, revealing that autoantibodies against the protein leiomodin-1 had the strongest association with NS; specifically, leiomodin-1 autoantibodies were found in 53% of NS cases compared to 31% of controls (OR: 2.7; 95% CI: 1.1-6.5) [ 43]. However, a recent study could not confirm the association between autoantibodies against leiomodin-1 and NS [ 44].

One study found no autoantibodies against N-methyl-D-aspartic acid (NMDA) receptors or the voltage-gated potassium channel (VGKC) complex in the serum of any NS cases tested [ 40].

Finally, another case-control study found that the mean plasma levels of macrophage migration inhibitory factor (MIF) were significantly elevated (47.3 ± 25 ng/mL vs. 17.8 ± 6 ng/mL) in NS cases compared to the healthy controls, which was hypothesized to play a role in the development and disease progression as a result of autoimmunity and neuroinflammation [ 45]. However, the frequency of MIF −173 C genotypes (CC/CG) was significantly lower in NS cases compared to the healthy controls (OR 0.33; 95% CI 0.14-0.8) [ 45].

3.2.5. Hormonal, Metabolic, and Genetic Factors

With respect to hormonal imbalances, a case series of Ugandan adolescents reported low levels of the peptide hormone somatomedin C (also known as insulin-like growth factor-1) in two out of eight NS cases. This study also reported low levels of luteinising hormone, follicle-stimulating hormone, and the sex hormones testosterone and oestrogen in seven of eight cases [ 46]. In contrast, all eight cases had normal levels of other hormones, including thyroid hormone, parathyroid hormone, growth hormone, adrenocorticotropic hormone, adrenal corticosteroids, and mineralocorticoids [ 46, 47]. Finally, a case-control study found no association between serum serotonin level and NS [ 48].

Altered metabolism was identified as a possible cause of NS by a case series involving 48 Ugandan patients with low mean levels of biotinidase and acetyl carnitine, but normal urate levels [ 49]. In addition, another case series involving 10 Ugandans reported high anion gap metabolic acidosis [ 47].

With respect to genetic aetiological factors, one case-control study in South Sudan (with 48 cases and 51 controls) found that the presence of specific amino acids at specific positions in the HLA-B (Ala11, Ala24, Asn63, and Phe67), DRB1 (Ala73 and Thr77), and DQB1 (Pro56, Glu66, and Val67) proteins were significantly associated with increased susceptibility to NS, while other specific amino acids in the HLA-B (Ser11 and Glu63), HLA-C (Trp156 and Glu163), DRB1 (Lys71, Gly73, Arg74, and Asn77), and DQB1 (Leu56, Asp66, Ile67, Glu70, and Asp71) proteins were associated with a decreased risk of NS [ 50]. A separate, relatively small case-control study (with three cases and five controls) of Ugandan children reported normal mitochondrial DNA and negative oligonucleotide microassay results for consanguinity, deletion, and duplication [ 39].

3.3. Pathophysiology

One autopsy study of five deceased NS cases in Uganda suggested that NS may represent a new form of tauopathy based on the presence of tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like tau in the cerebral cortex, brain stem, and basal ganglia of all five cases [ 51]. However, another autopsy study of another five Ugandan cases could not confirm these findings; instead, the authors proposed a neuroinflammatory pathophysiology, as they found no signs of generalised tauopathy, but rather found cerebellar atrophy, a loss of cerebellar Purkinje cells, cortical gliosis, and features indicating previous ventriculitis and/or meningitis [ 52]. This conclusion based on neuroinflammation was consistent with the findings of six separate magnetic resonance imaging (MRI) studies involving 66 cases, which found gliosis (mainly in the occipital and parieto-occipital areas) and cerebellar atrophy, with no focal changes in the cerebral cortex or hippocampus [ 4, 14, 29, 34, 39, 53]. This neuroinflammation did not appear to be the result of a chronic infection in the central nervous system (CNS), as six studies (with a total of 148 cases) reported normal cell counts, protein levels, and glucose concentration in the CSF [ 4, 14, 29, 31, 33, 39]. Interestingly, one of these six studies reported the presence of oligoclonal bands in the CSF-which indicates the presence of immunoglobulins that are commonly found in a wide range of neuroinflammatory diseases-in one of the three cases in their study [ 39].

No cytokine-specific profile was identified in any of the NS cases; however, one case-control study reported higher levels of the cytokine-like polypeptide C5a in the CSF of NS cases compared to controls, suggesting complement activation [ 54]. The same study also found lower plasma levels of CCL2, CCL5, CXCL13, IL-10, APRIL (also known as TNFSF13), and MMP-9 (matrix metallopeptidase 9) in NS cases compared to controls [ 54]. Another study reported decreased levels of IL-13 in NS cases, but could not detect IL-5, IL-6, or TNF-α [ 55].

Seven studies (with a total of 111 cases) reported findings based on electroencephalogram (EEG) recordings and found evidence of atonic seizures (i.e., presence of electro-decrement and paraspinal electromyographic dropout) in patients who experienced nodding episodes during the EEG recordings [ 14, 53]. In addition, EEG recordings also showed evidence of generalised and focal seizures [ 4, 14, 18, 26, 29, 39, 53].

With respect to nonspecific laboratory findings, several case series reported low haemoglobin levels [ 4, 10, 47], elevated eosinophil counts [ 4, 29], and increased erythrocyte sedimentation rates [ 4] in NS cases. In contrast, liver function, kidney function, white blood cell counts, and platelet counts were all normal [ 4, 29, 47].

3.4. Clinical Features

Prior to the onset of typical head-nodding seizures, 20% of NS cases seem to develop prodromal signs, including an expressionless stare, excessive sleepiness, dizziness, and loss of attention [ 4, 30, 56]. The characteristic involuntary repetitive head nodding-which may be present in all NS cases-likely results from a periodic loss of neck muscle tone [ 13, 14, 18, 30]. The onset of these symptoms has been described in both children and young adults ranging from 2 to 22 years of age, with a slightly higher prevalence among males (55%) [ 4, 10, 13, 14, 16, 19, 25, 26, 31]. In the majority of cases, head nodding is reported to be triggered by the sight of food or by cold weather [ 4, 14, 16, 18, 29, 30, 46, 57].

In over 80% of cases, NS progresses to include other seizure types, including generalised tonic-clonic seizures, partial complex seizures, and atypical absence seizures [ 4, 12, 14, 16, 18, 21, 26, 29, 53, 56]. In addition, approximately 30% of patients develop cognitive impairment, which can present as a slow reaction time, depression, and/or dropping out of school [ 4, 12, 13, 14, 16, 18, 24, 26, 30, 56, 57, 58]. Impaired physical development is also reported, including stunted growth with delayed bone age (41% of cases), wasting (73% of cases), and delayed puberty [ 4, 13, 16, 24, 46, 56, 58, 59].

Further complications reported to be associated with NS include psychiatric symptoms such as mood changes, aggressiveness, sleep disturbances, and wandering in 36%, 27%, 23%, and 9% of cases, respectively, as well as catatonia symptoms (e.g., staring, mutism, stupor, and grimacing) in some cases [ 4, 58, 60]. In contrast, neither focal neurological abnormalities nor cranial nerve palsies have been reported in NS [ 4, 13, 14, 30].

Some patients were described to progress to even more severe forms of NS, although the percentage of patients who do so is currently unknown. Children with a severe form of NS are often severely mentally retarded with impaired speech or a complete loss of speech, the inability to stand, urinary incontinence, a tendency to wander, and Parkinson-like features such as drooling, facial masking, facial tics when speaking, and slow speech patterns [ 4, 10]. These patients may die due to uncontrolled generalised seizures or other events such as falling into the fire while cooking or drowning [ 4, 10, 12, 13, 14, 18, 29, 56, 58]. To date, no reports of children making a full recovery from NS have been published.

3.5. Diagnosis and Management

Currently, no laboratory test is available to confirm the clinical diagnosis of NS. However, in 2012 a consensus case definition was established during the International Scientific Meeting on Nodding Syndrome held in Kampala, Uganda [ 9], which was modified in 2013 during the single-stage cluster survey conducted by the CDC and the Ugandan Ministry of Health to determine the prevalence of NS in Uganda ( Table 6 ) [ 19]. This definition is now used widely by clinicians and scientists. Prior to 2012, however, characteristic repetitive head-nodding seizures were used to diagnose NS.

Table 6

Suspected Case:

Reported Head Nodding in a Previously Healthy Person. Head Nodding Is Defined as Repetitive, Involuntary Drops of the Head towards the Chest on Two or More Occasions

Probable case

Suspected case of head nodding, with one major criterion plus at least one minor criterion
Major criteria:

3-18 years of age at the onset of nodding

Minor criteria :

Other neurological abnormalities (cognitive decline, school dropout due to cognitive/behavioural problems, other seizures or neurological abnormalities)

Clustering in space or time with similar cases

Triggered by food or cold weather

Psychiatric manifestations

Confirmed case

Probable case, with documented head-nodding episodes based on:

Observation and recording by a trained healthcare worker, or

A videotaped head-nodding episode, or

Video/EEG/EMG documenting head nodding as atonic seizures

Seven studies in our dataset reported on the management of NS. Five of these studies found that the use of anticonvulsants-including phenobarbitone, carbamazepine, sodium valproate, and phenytoin (either individually or in combination)-reduced seizure frequency in 70% of cases, with complete seizure control achieved in 25% of cases [ 13, 29, 53, 59, 61]. In addition, anticonvulsants were reported to increase basic self-care, behaviour, and school attendance in 80%, 59%, and 40% of cases, respectively, thus reflecting an increase in independence [ 61]. In one study, the combined use of anticonvulsants and multivitamins was reported to reduce wasting and stunting [ 59]; however, whether these interventions affect disease progression in NS remains unknown. Finally, community-directed treatment with ivermectin combined with larviciding of rivers was reported to coincide with a reduction in the incidence of NS in northern Uganda [ 62].

3.6. Community Perceptions and Psychosocial and Economic Impact

Twelve qualitative studies (all of which were performed in Uganda) investigated community perceptions and the psychosocial and economic burden of NS.

3.6.1. Perceptions and Beliefs

Within communities, NS was perceived to be associated with a wide variety of factors, including living in a camp for internally displaced people [ 63, 64, 65]; consumption of expired and/or contaminated relief foods [ 64, 65, 66]; exposure to chemicals from war munitions [ 63, 64, 65, 67, 68]; evil spirits, being cursed, or punishment from the gods as a result of bad deeds committed during a time of war [ 58, 63, 64, 65, 66, 67, 69]; open-gold mining in Karamoja region (northeastern Uganda) polluting the rivers with heavy metals such as mercury [ 65]; and blackflies breeding in the rivers in northern Uganda [ 63, 67].

3.6.2. Transmission, Presentation, and Treatment

In some studies, communities reported the belief that NS can be transmitted from person to person through saliva and the air [ 58, 63, 64, 66, 68]; therefore, patients with NS are often isolated from their family members and peers (e.g., eating and sleeping separately) in NS-affected communities. Some communities reportedly perceive NS as a distinct disease entity from epilepsy, given that NS is generally more severe and can include severe mental and/or physical disabilities [ 66, 68]. Furthermore, local communities in northern Uganda reported believing that NS cannot be cured [ 58, 63, 69] and that anticonvulsive medications-particularly sodium valproate-are associated with promiscuous behaviour, resulting in low treatment compliance [ 70].

3.6.3. Health-Seeking Behaviour of Caretakers

Caretakers generally seek healthcare from government health facilities; however, a shortage of healthcare workers, long waiting hours, frequent lack of medicines, and transport-related issues (e.g., a lack of money for transportation and/or difficulties associated with transporting mentally and physically disabled patients with NS) often drives caretakers to seek care from traditional healers and witch doctors [ 70, 71].

3.6.4. Psychosocial and Economic Burden

The mental and physical impairments caused by NS often lead to personal and family shame [ 70, 72], discrimination, social isolation [ 65, 66, 67, 72], and economic constraints due to reduced livelihood activities [ 66, 67, 68, 72]. In addition, caretakers experience poor sleep and are often depressed, which can lead to domestic violence, substance abuse, and suicidal and homicidal thoughts, potentially ending in family separation [ 66, 67, 68, 72]. Some caretakers report feeling that their children with NS are useless [ 65, 69]. In addition, children often drop out of school due to fears related to the person-to-person transmission of NS [ 66, 67]. Finally, some individuals with NS report being sexually abused, exploited, or forced to engage in child labour [ 70].

4. Discussion

Nodding syndrome is an unexplained, currently untreatable, and devastating neurological disease currently affecting thousands of individuals in various sub-Saharan African countries. Despite the high burden placed on affected individuals and their families, NS has received strikingly little attention; moreover, the available information is scattered throughout the literature, thus prompting the need for this scoping review in which we summarise the evidence to date and reveal research and knowledge gaps. The paucity of knowledge regarding NS is due primarily to a lack of funding to conduct studies in NS-affected areas, which are often challenging due to access constraints, civil conflicts, poverty, and a lack of trained personnel. In addition, NS has been a largely neglected disease even though it leads to significant physical, mental, and socioeconomic impairments.

The first cases of NS were reported in Tanzania in the 1930s; today, however, South Sudan is considered to have the highest number of cases [ 3, 10, 16, 18, 19, 20, 21]. Thus, the epidemiological picture is still changing, with new cases emerging in South Sudan (in Mundri West County and Mundri East County; our unpublished observations), and hardly any new cases reported in southern Tanzania (Mahenge, Ulanga district) [ 73] and northern Uganda (Kitgum and Pader districts) [ 62]. However, due to the paucity of large-scale studies, solid epidemiological data from affected countries and regions are not available to support these anecdotal observations or establish the true burden of NS. Interestingly, new cases of NS were reported recently in the DRC (in 2016), Cameroon (in 2018), and the Central African Republic (in 2019) [ 16, 17, 20], suggesting that NS may be prevalent in many more countries than previously known.

With respect to the underlying cause of NS, many factors have been associated with NS and suggested as potential causes; however, to date none of these have been shown definitively to cause NS. Nevertheless, the putative association between NS and infection with the filarial nematode Onchocerca volvulus (OV) has gained considerable interest. This is not surprising, as this is the only association consistently identified by multiple studies [ 12, 18, 30, 31]. However, one should be careful not to overinterpret this association or consider it definitive evidence of a causal relationship. From a pathophysiological perspective, it seems unlikely that OV invades the CNS. Although early studies detected small numbers of OV nematodes in the CSF of patients following treatment with the anthelmintic drug diethylcarbamazine [ 74], the normal biochemical profile of CSF and the inability of recent studies to detect OV or Wolbachia filarial endosymbionts in the CSF using microscopy or PCR seems to rule out the likelihood of CNS infection [ 12, 29, 33, 34]. An alternative pathophysiological mechanism was suggested to involve an autoimmune response induced by OV infection, for example the so-called leomodin-1 hypothesis [ 43]. Because leiomodin-1 shares high homology with an OV-like protein, and because autoantibodies have been shown in vitro to induce neurotoxicity, a possible mechanism involving molecular mimicry induced by OV infection has been hypothesised. Several findings, however, makes this an unlikely possibility. First, healthy controls living in the same villages as NS cases also have antibodies, at only a marginally lower prevalence. Second, no association has been found between OV status and anti-leiomodin-1 antibody levels. Finally, whether the leomodin-1 protein is localised to the extracellular side of CNS cells has been debated [ 75, 76].

On the other hand, the repeated findings of an apparent association between OV infection and NS should not be ignored. For example, given that NS is likely multifactorial, OV infection may be only one piece of the puzzle and may require additional factors such as immunosuppression due to malnutrition, toxins (e.g., mycotoxins), and/or genetic predisposition such as a specific HLA haplotype, as recently suggested [ 50]. Alternatively, rather than playing a causal role, OV infection may be a confounding factor associated with a yet-to-be-determined cause. For example, NS may be caused by an unidentified neurotropic virus transmitted by the same vector as OV (i.e., blackflies). Another possibility is a converse causal relationship between OV and NS, in which patients with NS may have an increased risk of becoming infected with OV; this is certainly plausible, given that individuals with NS are often isolated, drop out of school, and have a tendency to wander off, thus increasing their exposure to blackflies. Clearly, future studies are needed in order to investigate these causal relationships, as well as potential confounders and the interaction with OV.

The possible association between prior measles exposure and NS is particularly interesting given certain similarities between NS and subacute sclerosing panencephalitis (SSPE), a chronic progressive brain inflammation occurring years after infection with a hypermutated strain of the measles virus. A previous study suggested an association between NS and SSPE based on the finding that both NS and SSPE affect children at around the same age and have the same gender bias, as well as the finding that NS cases often increase following a peak in measles cases [ 35]. On the other hand, NS and SSPE differ in several aspects. First, the head nodding in NS is triggered by food and cold weather, whereas the initial myoclonic head jerks in SSPE are triggered by excitement [ 77]. Second, unlike SSPE, NS does not present with focal neurological or visual impairment [ 77]. Third, the CSF in children with NS is often normal, while gamma globulin levels are often increased in the CSF in SSPE (representing more than 20% of total CSF proteins) [ 77]. Fourth, the above-mentioned studies used the reported history of measles infection, which can be prone to many types of bias. In summary, it seems unlikely that NS is caused by SSPE, although further study is clearly needed. In addition, NS may actually be caused by an SSPE-like pathophysiological mechanism caused by a different virus. Given that viral infections have not yet been investigated in detail, this notion warrants further study.

The reported putative association between low levels of vitamin B6 (specifically, pyridoxal-5-phosphate) and NS [ 38] is potentially relevant, as severe vitamin B6 deficiency can cause convulsions [ 78, 79]. However, three studies were unable to confirm this association [ 31, 39, 40], although one study found that vitamin B6 deficiency was common throughout the entire study population. Low levels of vitamin B6 in NS cases could be a complication of the disease, rather than an aetiological factor. Because humans cannot synthesise vitamin B6, it must be provided by dietary sources; however, patients with NS often have poor eating habits due to sleepiness and because eating can trigger nodding seizures. On the other hand, given that NS does not appear to be associated with deficiencies in vitamin A, vitamin B12, folate, zinc, or selenium, dietary factors are less likely. Future studies are therefore warranted in order to re-evaluate the association between NS and vitamin B6; ideally, such studies should include cases in the early stages of disease in order to minimise the decrease in dietary intake that results from NS. Moreover, vitamin B6 is a complex consisting of six separate vitamers, of which only one (pyridoxal-5-phosphate) has been studied; thus, measuring the levels of all six vitamers in the plasma and CSF may provide new pathophysiological insights.

Several toxins have also been suggested to play a role in NS; however, the epidemiological data do not appear to support this association. Although Spencer et al. previously suggested that mycotoxins in grains consumed during times of displacement in South Sudan may be associated with NS [ 12], similar grains were also consumed by other displaced persons in other regions within South Sudan, with no reported cases of NS. Moreover, the same group recently reported that both children with NS and children without NS harbour foodborne mycotoxins [ 42]. Similarly, the use of crushed plant roots in traditional medicines seems unlikely to be the cause of NS, as they are used widely around the world [ 80]. Lastly, chemicals from war munitions, which were identified as a possible cause of NS in Uganda, were not found to be associated with NS in South Sudan, which experienced more than 21 years of civil war and never reported a single case of NS in their most war-affected areas, including the Eastern Equatoria State.

Interestingly, the presence of low average levels of biotinidase and acetyl carnitine detected in a few NS cases in Uganda suggests a possible metabolic cause [ 49]. However, carnitine deficiency-related encephalopathies are often accompanied by skeletal muscle myopathy and cardiomyopathy, neither of which is typically seen in NS [ 81]. Similarly, biotinidase deficiency is an unlikely cause of NS, as it usually presents with vision and hearing loss, cutaneous abnormalities, and hypotonia, none of which are typically seen in NS [ 82]. Nonetheless, a thorough evaluation of metabolic changes is warranted in order to definitively include or exclude their role in the aetiology of NS.

Autopsy studies will likely play an essential role in determining the underlying pathophysiology of NS through examination of postmortem histopathological patterns and confirmation of the antemortem microbiological diagnosis; however, only two autopsy studies have been reported to date. The first study suggested that NS may represent a new form of tauopathy [ 51], as the result of either the NS disease itself or the underlying repetitive seizure activity [ 83, 84]. In contrast, the second autopsy study concluded that NS may be the result of a generalised neuroinflammatory pathophysiological process [ 52]. A general limitation of both autopsy studies is the relatively small number of cases (with only five cases each), making it difficult to draw any clear conclusions. Finally, other pathophysiological studies using MRI, EEG, and generalised laboratory tests also failed to provide any insights into the pathophysiological mechanisms underlying NS.

NS was recently suggested to be part of a spectrum of diseases known as onchocerciasis-associated epilepsy (OAE), which is defined as two or more seizures with no obvious cause occurring between the ages of 3-18 years in a previously healthy person who had lived for at least 3 years in an onchocerciasis-endemic area [ 57]. NS may indeed be a subtype of OAE, given the similar epidemiology, the fact that both are epileptic disorders, and the fact that both are associated with OV infection. The proposed differential diagnosis of OAE includes NS, Nakalanga syndrome (defined as epilepsy with impaired growth, physical deformities, endocrine dysfunction, and mental impairment), and other forms of epilepsy such as epilepsy in onchocerciasis-endemic areas. However, given that NS has not been shown definitively to fit within the OAE spectrum with a similar pathophysiological mechanism, for the purposes of this scoping review, we limited the evidence to patients with NS.

No cure currently exists for NS. However, based on the relatively few intervention studies conducted to date (albeit without a control group for comparison), the ideal management of NS would likely include prophylactic anticonvulsants, nutritional supplementation, physiotherapy and rehabilitation, and psychosocial support for the patient and his/her family. Such an approach would require a multidisciplinary team of specialists, which is currently difficult to implement in the resource-poor areas in which NS is endemic. On the other hand, community-guided administration of ivermectin combined with application of larvicides to rivers in northern Uganda has been shown to coincide with a reduction in the incidence of NS [ 62]. However, whether this reduction in NS cases was due to larviciding the rivers (thus reducing blackfly populations), ivermectin treatment (thus reducing OV microfilaria load), and/or another unrelated factor remains an open question. Clearly, carefully controlled studies are warranted in order to explore the possible effect of each of these factors.

The major limitation in our inclusion criteria was that we only included publications in English language, which excluded any relevant publications in other languages.

5. Conclusions

In light of the relatively limited data reported on NS to date, more studies are needed in order to increase our knowledge regarding this devastating yet often neglected disease. In this respect, large population-based studies spanning sub-Saharan Africa will likely provide a more complete picture of the true burden of NS. In terms of aetiology, future studies should focus on examining a wider range of possible factors, including metabolic, nutritional, autoimmune, genetic, viral, and other infectious agents, as well as potential interactions between these factors. Follow-up studies are also needed in order to differentiate between potential causal associations with OV, confounding factors, and/or other previously associated factors. In addition, studies involving animal models may help to test emerging hypotheses regarding causal factors. Moreover, postmortem studies including larger numbers of well-preserved samples will likely provide valuable information regarding the underlying pathophysiology, and randomised controlled trials are needed in order to evaluate new treatment options such as anticonvulsants and micronutrient supplementation. Finally, innovative programmes designed to address the psychosocial and economic impacts of NS, as well as rehabilitation strategies, are urgently needed.

Author Contributions

The author contributions include conceptualization, G.O.E.A.-E.; A.W.D.E.; R.S. and M.B.v.H.; literature search, G.O.E.A.-E. and R.S.; screening, G.O.E.A.-E. and A.W.D.E.; data extraction, G.O.E.A.-E.; writing-original draft preparation, G.O.E.A.-E.; writing-review and editing, G.O.E.A.-E.; A.W.D.E.; M.B.v.H.; R.S. and M.B.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Foreign Affairs, Government of the Netherlands (0079 SSNSS).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data are included in this manuscript. There is no other data involved in this study.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

9. WHO . International Scientific Meeting on Nodding Syndrome Kampala, Uganda. WHO; Geneva, Switzerland: 2012. pp. 1-42. [ Google Scholar]

19. Iyengar P.J., Wamala J., Ratto J., Blanton C., Malimbo M., Lukwago L., Becknell S., Downing R., Bunga S., Sejvar J., et al. Prevalence of nodding syndrome-Uganda, 2012-2013. CDC MMWR-Morb. Mortal. Wkly. Rep. 2014;63:603-606. [[ PMC free article] [ PubMed] Google Scholar]

80. WHO . Traditional Medicine. In: ASSEMBLY F-SWH, editor. Provisional Agenda Item 1410. WHO; Geneva, Switzerland: 2003. [ Google Scholar]

82. Wolf B. Biotinidase Deficiency. In: Adam M.P., editor. GeneReviews. Volume 1993-2021 University of Washington; Seattle, WA, USA: 2016. [ Google Scholar]

Articles from Tropical Medicine and Infectious Disease are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

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Nodding syndrome (NS) is a debilitating yet often neglected neurological disease affecting thousands of children in several sub-Saharan African countries. The cause of NS remains unknown, and effective treatment options are lacking. Moreover, knowledge ...

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National Public Radio Organization's Article about Nodding Syndrome

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National Public Radio Organization's Article about Nodding Syndrome

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This article talks about curing efforts in Uganda and nurse's experiences with children. Published in 2023

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Ventorina Aculu, a mother of eight in her 60s, says she is proud to have given birth to her many children. Her distress only set in with her last two, both sons and now adults. Omac Alfred and Kibwota Johnson, both in their 20s, began to show signs of a rare disease in their infancy - a little understood neurologic condition characterized by repetitive head nodding and accompanied by a raft of other grave symptoms - which has now haunted the family for two decades.

"I don't know what I am treating. They have been on medication, but their situation has continued to deteriorate year in and out due to a worsening health condition," she told Undark. "When one goes to the hospital or gets medication, the goal is to see change, but with me here, I don't see any."

"At my age, these young stars should have been the ones looking after me," Aculu added. "But unfortunately it's me laboring with them."

Omac and Kibwota suffer from nodding syndrome, a neurological disease for which the cause has not yet been conclusively identified. In northern Uganda, a region fraught by years of civil war, the disease reached epidemic proportions between 1997 and 2012, then declined. Many experts believe nodding syndrome is related to the parasitic roundworm Onchocerca volvulus, even if indirectly. The World Health Organization has noted that there's strong evidence that river blindness, an illness caused by the roundworm, which is transmitted by black flies, is connected.

But some scientists say this conclusion is premature, instead arguing for other possible causes, including malnutrition and even the consumption of a toxic mushroom. The stakes are high for the roughly 2,100 nodding syndrome survivors in northern Uganda - and countless others in places where the numbers are even less firm, such as South Sudan. A lack of understanding of the disease's origins could delay current treatment and perhaps even the scientific know-how needed to combat the next nodding syndrome epidemic.

Still, many experts support the theory that nodding syndrome is related to O. volvulus infection. "I think there's an interesting story there about what happened and the impact on people in northern Uganda and what was learned about the cause of the syndrome and how it was ultimately resolved or largely resolved," said Scott Dowell, a former epidemiologist at the Centers for Disease Control and Prevention, and a nodding syndrome expert.

Suzanne Gazda, a Texas-based neurologist who ran the nonprofit Hope for Humans, isn't as optimistic. Hope for Humans focused on care for nodding syndrome sufferers in northern Uganda from 2012 to 2017, when it ceased operations. Gazda reflected on the apparent hopelessness of the situation and what she described as piecemeal advancements in the scientific understanding of the disease. "We've got to help these children that have been abandoned and essentially left to suffer and die," she said. "But every place I went, people were interested, but there was no follow up."

Nodding syndrome is usually described as a debilitating neurological disease that almost exclusively manifests in children and young adults (ages 3 to 15). But while it leads to severe symptoms related to the brain, including periodic head nodding and violent epileptic seizures, it can also cause bouts of excessive sleepiness and dizziness, loss of attention, stunted physical growth, body wasting, delayed puberty, and depression. It is these symptoms that Aculu said are particularly difficult as she cares for her adult sons.

It's not clear when nodding syndrome in its current form was first known to scientists; some researchers argue it was first described in Tanzania in the 1960s, and others as far back as Mexico in the 1930s. Still, assuming nodding syndrome is associated with O. volvulus, it may have been present as far back as the 1870s - when onchocerciasis, or river blindness, was first described by doctors.

O. volvulus is a parasitic roundworm, or filarial nematode, which causes river blindness - a disease that can include visual impairment, severe rashes, and, rarely, swollen lymph nodes. A relationship between that illness and nodding syndrome is supported by descriptions of patients with the latter suffering from epilepsy and related neurological difficulties.

The most exhaustive battery of exams conducted on Ugandan nodding syndrome sufferers occurred in the spring of 2014. The voluntary participants - a family of eight, three of whom had nodding syndrome - were transported to National Institutes of Health facilities in Maryland for two weeks. Virtually every nodding syndrome research group drew conclusions from the family's test results: The patients had a history of O. volvulus infections and exhibited borderline low levels of the vitamin B6, which likely helps with brain function by lowering levels of a protein linked to dementia and cognitive decline. Two also experienced brain atrophy. Yet genetic testing ruled out hereditary epilepsy and other brain diseases.

"These were truly groundbreaking results," said Avindra Nath, an NIH researcher who led much of the work. "We hope that we provided at least one avenue for research and a new direction for it, but there's still lots to be studied."

While the results have so far not pointed to a specific cause, many researchers contend that river blindness causes nodding syndrome. Harkening back to the possible descriptions of nodding syndrome in the 1930s, Robert Colebunders, a Belgian researcher at the University of Antwerp, sees a pattern. "It's extremely the same description," he said.

Colebunders and his colleagues offer several arguments for the claim that nodding syndrome is caused by the parasitic roundworm. For instance, they contend that the areas where nodding syndrome is predominant in northern Uganda, as well as in documented cases in South Sudan and other countries in East and Central Africa, are also the breeding grounds for the Simulium black flies that transmit the parasite. These are regions that have also historically demonstrated high rates of transmission of onchocerciasis. And the researchers also point out that the key feature of nodding syndrome - the seizures - is not unheard of in river blindness sufferers.

Other researchers agree that O. volvulus is likely involved with nodding syndrome, but with caveats. "There's clearly an association with the onchocerciasis, but that only gets you so far," said Dowell, the former CDC researcher who is now a deputy director with the Bill and Melinda Gates Foundation. River blindness, he added, is caused by a worm, and "worms don't usually cause seizures."

Dowell and his colleagues point out that people with nodding syndrome typically show no sign of the roundworm's presence in their spinal fluid, an indication of active infection that could affect the brain. A majority of patients who have had skin snips performed - a small biopsy for sample purposes - have shown traces of previous river blindness infection, but most aren't active cases.

These researchers say the disease is instead an example of molecular mimicry. In other words, the immune systems of patients may be reacting to O. volvulus infections. Essentially the body begins to attack healthy proteins responsible in shaping its cells because they resemble antibodies that form in response to the parasite's presence. The victim's neurons can become a casualty in this theorization of the disease, causing permanent damage. In this way, the worms never actually make their way directly to the human brain, say as in the case of cysticercosis, caused by the pork tapeworm. (Colebunders countered that he's still not convinced that it is mimicry rather than the worms themselves. He argues that a lack of a positive skin or spinal fluid test for onchocerciasis among individuals with nodding syndrome in later age doesn't mean they weren't infected by the parasite years or even months before.)

At least as far back as 2012, the CDC and WHO noted the possibility that nodding syndrome is associated with onchocerciasis on their websites. And in a report on a December 2022 meeting on onchocerciasis, the WHO noted that there's strong evidence for a connection between nodding syndrome and river blindness. While the group has not yet issued any formal recommendations, Maria Rebollo Polo, of WHO's Global Program for Elimination of Onchocerciasis, told Undark in an email that she is planning a meeting either this year or next to address next steps.

Some interventions on the ground suggest the disease can be curbed by eradication efforts against black flies and the roundworm. In northern Uganda starting in 2009, efforts to control Simulium fly populations and the distribution of anti-parasitic drugs like ivermectin were rolled out in many rural villages affected by onchocerciasis. Since then, new cases of nodding syndrome have decreased dramatically.

It's a step in the right direction as far as Colebunders is concerned. While questions remain regarding the disease's origins "and it's good that researchers can continue," he said, it's still important for that research "to continue in the right way."

The priority, he added, is to eliminate onchocerciasis everywhere.

Not all researchers are convinced of a nodding syndrome-river blindness association. To begin with, onchocerciasis is present in three distinct geographies: the Amazon Basin, Yemen, and sub-Saharan Africa. Yet no clinically described cases of nodding syndrome have been recorded in the Amazon or Yemen. And nodding syndrome does not appear to cause one of the key features of river blindness: vision impairment.

Other doubts persist as well. While studies have shown that individuals with nodding syndrome, including in northern Uganda, have been infected by O. volvulus in the past, this is not always the case. In some research, the link between previous roundworm infection and the disease isn't even statistically significant.

There is also the issue of the black flies. Joe Otoo is a village health team member who first encountered nodding syndrome in northern Uganda's Kitgum district in 1998. Team members like Otoo help with mobilizing communities to gain better health care from Uganda's regional and central governments.

Of the idea that black flies are leading to nodding syndrome, Otoo said he disagrees because black flies have been around since he was young. Nodding syndrome, he said, has not.

Otoo and other families have long administered drugs to reduce the aggressiveness of their children's seizures and epilepsy, including carbamazepine, phenytoin, and phenobarbital. They also rely on folic acid and other supplements to help replenish patients' health, given the effect of the disease on their brains and bodies. Nevertheless, these families are merely treating the symptoms and still don't have clear insight into nodding syndrome's origin.

Such uncertainty drives the work of Peter Spencer, a neurology professor at Oregon Health and Science University who's been studying nodding syndrome for two decades. "What is the cause? We do not know," he told Undark. "Not just 'we' in my laboratory, but nobody knows what the cause is."

Over the past 20-plus years, both affected communities in Uganda and foreign scientists and doctors have posited a wide range of alternative theories for the origin of nodding syndrome, from chemicals leached from civil war-era munitions to malnutrition to contaminated food supplies in refugee camps. These camps, built for internally displaced people, were particularly common while Uganda's central government and Joseph Kony's Lord's Resistance Army were in violent conflict from 1987 into the 2010s.

Ventorina Aculu harkens back to this era, referring to the "dark, demonic power" in her community as thousands of people were killed. But she also mentions the food her young boys ate in the camps at the height of the hostilities.

Toxins in the camps' food supply have been heavily disputed as a cause for nodding syndrome, but a new line of research has highlighted the possibility that malnutrition and suppressed immunity, combined with the consumption of a neurotoxic mushroom, could be culprits. In a 2022 review article, Spencer and his colleagues, including Ugandan research assistant Caesar Okot, have pointed to an agaric mushroom called Agaricus bingensis ( Ayaa Kum Got or Atel in the local Acholi language). The scientists reported that the wide consumption of the fungus may have led to poor vitamin B6 absorption - one of the symptoms in the family from the 2014 NIH study - which ultimately could have also resulted in severe brain degeneration.

In the refugee camps, "there was not enough food, there was a challenge of nutrition," said Okot, who is also a former NGO programs manager with years of experience helping victims of nodding syndrome. "So people took risks due to that mushroom, even serving it to children. And even the elders were eating it."

Spencer references other possible associations, including moldy corn and patients' previous history of measles as possible further drivers of disease, perhaps interacting synergistically. In one of his studies, 50 nodding syndrome sufferers had higher rates of measles and exposure to moldy food compared to a control group.

As Spencer's team noted in their 2022 review, more work has to be done to investigate these other possible causes. Over the last four years, NIH grants at least partially earmarked for nodding syndrome have totaled more than $2.3 million, including work by Spencer's research group on environmental factors. Meanwhile, around that same time, Colebunder's research program at the University of Antwerp received more than $2.5 million from the European Research Council for work on the relationship between onchocerciasis and nodding syndrome. In parallel, almost 500 peer-reviewed scientific articles have been published on the disease since 2019.

These are all drops in the bucket compared to other diseases affecting Uganda. One NIH grant investigating Ebola virus disease, another disease that has also wreaked havoc in the country, received a higher award than all of those nodding syndrome grants combined.

Back in Lobwor Omor, Ventorina Aculu noted that her two sons have undergone countless studies, and while they take anti-seizure medication to control the disease's acute symptoms, she's doubtful that they do much.

"Government gave us some medicine to give them, I don't know what it is, but nothing has changed," she told Undark.

Otoo isn't alone in this observation. Aber Salume, a registered nurse who works at the nearby Archbishop John Baptist Odama Care Center for children with nodding syndrome, provides her perspective on some of the most troubling manifestations of the disease: Most of the children enrolled at the center are those in severe form, she said: "Children who have developed psychosis, those who are psychiatric patients," and those who "are victims of developmental retardation."

At the center, for example, Salume added, a 27-year-old with nodding syndrome "cannot perform something that a child of two years old or one years old can perform."

And then there are people like Peter Paul Togero, who lives in the dusty village of Ayom in northern Uganda. He agreed that very little has been resolved. Togero is a member of an association of 43 parents with children suffering from nodding syndrome. "If you can, ask any organization to look for the solution of those who have the syndrome," he said. "If any organization can come and assist those, they are key."
Sam Schramski is a freelance journalist whose work has been featured at NPR, Mongabay, and Deutsche Welle among many others. Pat Robert Larubi is an independent investigative journalist, photographer, and television news and documentary film producer in Uganda.

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They're trying to cure nodding syndrome. First they need to zero in on the cause

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Nodding syndrome is a rare neurological condition that can result in head nodding and violent seizures. Some researchers think they know the cause, but questions remain.