Nodding syndrome (NS) is a debilitating yet often neglected neurological disease affecting thousands of children in several sub-Saharan African countries.
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][1][2][3][4].
2. 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][5]. These early reports were followed decades later by reports from Liberia
[11][6], southern Sudan (now officially known as the Republic of South Sudan)
[3[3][7],
12], western Uganda
[13][8], and northern Uganda
[14][9] (
Figure 31). Recently, NS was reported in regions within the Democratic Republic of Congo (DRC)
[15][10], Cameroon, and the Central African Republic
[16,17][11][12] (
Figure 31).
Figure 31. African countries in which cases of NS have been reported, including the first year in which they were reported. The inset shows the reported prevalence of NS in the indicated countries.
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[3][13],
18], northern Uganda (Kitgum, Pader, and Lamwu districts)
[19][14], the DRC (town of Aketi)
[20][15], and Tanzania (Ulang district and Morogoro region)
[21][16], 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][11]. Finally, in the Central African Republic, a total of five cases were identified among 6175 individuals
[17][12].
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][7][10][11][13][15][17][18][19][20] and in families, with some families having two or more affected members
[3,10,19,26,27,28,29][3][5][14][21][22][23][24]. In addition, NS has also been associated with poverty, food shortage, and a history of displacement
[12,18,23,25][7][13][18][20].
3. 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.
3.1. Infection
With respect to parasitic infection, most studies focused on
Onchocerca volvulus (OV) infection (
Table 31) 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][7][13][25][26]. 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][27]. 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][7][24][28][29] or species of
Wolbachia (an endosymbiotic bacteria that occurs together with OV) in CSF samples taken from 10 NS cases
[33][28]. 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][7] (
Table 31). 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][7][26].
Table 31. Case–control studies reporting associations between pathogens and nodding syndrome.
Pathogen |
Location |
Test |
Cases |
Controls |
Odds Ratio (95% CI) |
p-Value |
Reference |
53. Case–control studies reporting associations between toxins and nodding syndrome.
Toxins |
Location |
Test |
Cases |
Controls |
Odds Ratio (95% CI) |
p-Value |
Reference |
Country |
Area (Year) |
N |
% |
N |
% |
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][7 |
Mouldy maize |
Uganda |
Kitgum (2014) |
DtH | ] | [ |
50 | 13 | ] |
|
50 |
Amadi (2001) |
SSM |
30 |
96.7 |
34 |
50 |
29 (3.5–237.7) |
- |
[18][13] |
Lui (2002) |
SSM |
13 |
92.3 |
16 |
43.7 |
15.4 (1.6–148.8) |
0.008 |
[12,18][7][13] |
Maridi and Witto (2011) |
SSM |
38 |
76.3 |
38 |
47.4 |
3.2 (1.2–8.7) |
0.02 |
[30][25] |
Uganda |
Kitgum (2009) |
SSM |
45 |
71.1 |
39 |
53.9 |
1.11 (0.37–3.27) |
- |
[31][26] |
|
4.33 (1.4–18.9) |
0.009 |
[ | 35 | ] | [ | 31 | ] |
Maize |
Uganda |
Kitgum (2014) |
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) |
|
Kitgum and Pader (2016/17) |
Ov16 IgG |
154 |
93.5 |
153 |
54.9 |
8.79 (4.15–18.65) |
0.001 |
[37][30] |
Mansonella perstans |
South Sudan |
Lui (2001) |
BM |
39 |
41 |
31 |
9.6 |
3.2 |
0.005 |
[12][7] |
Amadi (2001) |
BM |
30 |
66.6 |
34 |
50 |
Loa loa |
South Sudan |
Lui and Amadi (2001) |
BM |
69 |
0 |
65 |
0 |
- |
- |
[12][7] |
Wuchereria bancrofti |
South Sudan |
Lui (2001) |
BM |
39 |
0 |
31 |
9 |
- |
0.47 |
[12][7] |
Amadi (2001) |
30 |
0 |
34 |
7.6 |
- |
Trypanosoma brucei |
South Sudan |
Lui (2021) |
CATT |
39 |
12.8 |
31 |
9.6 |
0.84 |
0.94 |
[12][7] |
Amadi (2001) |
30 |
0 |
34 |
5.8 |
Uganda |
Kitgum (2009) |
CATT |
36 |
0 |
40 |
0 |
- |
- |
[31][26] |
Taenia soleum |
Uganda |
Kitgum (2009) |
Antibody |
36 |
0 |
40 |
0 |
- |
- |
[31][26] |
Measles virus |
Uganda |
Kitgum (2009) |
Past history |
|
23.5 |
|
6.1 |
3.3 (0.8–13.6) |
|
[31][26] |
PCR |
16 |
0 |
0 |
- |
- |
- |
South Sudan |
Lui and Amadi (2002) |
Past history |
13 |
15.38 |
19 |
58 |
0.13 |
0.025 |
[12][7] |
Uganda |
Kitgum (2014) |
Past history |
50 |
100 |
50 |
- |
6 (1.02–113) |
0.047 |
[35][31] |
Hepatitis E virus |
|
Kitgum (2009) |
IgM |
38 |
31.6 |
31 |
16.1 |
1.45 (0.37–5.58) |
- |
[31][26] |
|
IgG |
38 |
26.3 |
30 |
33.3 |
0.81 (0.24–2.75) |
- |