Nodding Syndrome: The Unresolved Mystery of a Pediatric Disease in Sub-Saharan Africa

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The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019 www.pidj.com | S67
Nodding syndrome is a mysterious neurologic illness of unknown
etiology, presenting with distinctive clinical features often at early age.
Currently, it affects children in restricted geographical areas in South
Sudan, Northern Uganda and Southern Tanzania and is associated with
high mortality and morbidity, especially in the children with severe dis-
ease. In this paper, we will give an outline of what is known about nodding
syndrome with respect to epidemiology, clinical presentation, etiology
and treatment. In addition, a possible approach to resolving the mystery is
presented.
(Pediatr Infect Dis J 2019;38:S67–S71)
EPIDEMIOLOGY
Nodding syndrome (NS) poses a major public health con-
cern in parts of Tanzania, Uganda and South Sudan, with thousands
of children affected.1–4 However, it is not a new disease. The first
reports describing possible NS cases came from southern Tanzania
in the 1960s.5,6 In the 1990s, cases were also reported from southern
Sudan (now South Sudan)4,6,7 and in the first decade of this century,
from western and northern Uganda.6,8 In addition, in 1983, a seizure
illness resembling head nodding was described among the Bassa
and Kpelle population in Liberia.9 The first symptoms of NS nearly
always occur when children are between 5 and 15 years of age,
although there have been reports of symptoms starting as early as 2
years and in adults up to 32 years of age.6,8,10–12
The reported NS prevalence varies by region and over time.
Western Equatoria State in South Sudan is considered to have the
highest prevalence of NS among children 5–18 years of age (4.6%
in 2002 and 8.4% in 2013).6,13,14 However, the 2013 prevalence
was obtained from a household survey, which used definitions
that included children with both NS and epilepsy without nodding
episodes. In Uganda, the overall prevalence of NS is estimated at
0.7% of children between 5–18 years of age, while in the Ugan-
dan district of Kitgum the prevalence was found to be much higher
(4.6%).11,15 The current burden of NS in Tanzania is not known.6
Presently, NS is found in the Ulanga district (southern
Tanzania), the Equatoria and Lakes states (South Sudan), and in
Kitgum, Pader and Lamwo districts (northern Uganda).6,16 Most
reports of new NS, defined as children in whom nodding episodes
are present for less than 12 months, are from South Sudan and from
4 new Ugandan districts (Gulu, Lira, Amuru and Oyam districts),
which have not reported cases in the past.6 In villages, NS tends
to cluster in families, with many families having more than one
child with NS or epilepsy without nodding episodes.5,6,11,12,14,17–19
Furthermore, it was observed that the NS-affected communities
are generally poor and often had a history of displacement as a
result of civil conflict.1
CLINICAL PRESENTATION
The early stage of NS is often characterized by the occur-
rence of a repetitive head nodding, with a frequency of 5–20 nods
per minute, which is the result of a brief loss of neck muscle tone
due to generalized seizure activity recorded by electroencephalo-
gram.8,10,17,18 Nodding episodes may be provoked by food and cold
weather8,10,17,18,20 and in 20% are preceded by prodromal symptoms,
including dizziness, inattention, excessive sleepiness or expres-
sionless staring when food is offered.17
When the disease progresses, which occur in over 80% of
cases, other types of seizures, including partial complex, generalized
tonic-clonic and atypical absence seizures may develop.10,12,15,17–19
In addition, 30% of children become mentally retarded, which may
present in the early stages with dull affect, slow reaction time and
school dropout.10,12,15,17–19,21,22 Wasting and growth retardation occur
in 73% and 41% of NS children, respectively.8,15,17,20,22 Psychiatric
manifestations are common and may include, wandering (9%),
aggressiveness (27%), sleep disturbances (23%), mood changes
(36%) and catatonia.17,19,22 On the other hand, focal neurologic
abnormalities, visual impairment and cranial nerve palsies are
uncommon.8,10,17,21
It is unknown, what proportion of NS cases progress to
severe disease, which is characterized by altered level of con-
sciousness, impairment or loss of speech, inability to stand, urinary
incontinence, drooling of saliva and delayed sexual maturity.8,10,17–20
Mortality is high at this stage; often as a result of continuing sei-
zures, severe burns or drowning. There have been no reports of any
child with NS recovering from the illness.
DIAGNOSIS
There are no laboratory markers or findings as to imaging
that can be used to diagnose NS. The diagnosis, therefore, can only
be made using clinical criteria, resulting in considerable confusion
and debate on the right case definition that should be used. For
example, some clinicians have included children with generalized
seizures, living in NS-endemic areas, in their NS study population
even when head nodding was not present. Their argument was that
NS may be part of a spectrum of a neurologic illness with epilepsy
as the hallmark. To overcome this confusion, a consensus was
reached in 2012 at the International Scientific Meeting on Nodding
Syndrome in Kampala, Uganda, on a case definition that should be
used in all future NS studies (Table 1).23
With respect to laboratory findings, around 20% of children
with NS are anemic, 45% have a raised eosinophil count and 80%
a raised erythrocyte sedimentation rate. But white blood cell and
platelet counts, renal and hepatic function tests and cerebrospinal
fluid (CSF) basic investigations (cells, protein and glucose) are
generally normal.10,17,24
Electroencephalographic (EEG) recordings are generally
abnormal in patients with NS, showing evidence of general-
ized and focal epilepsies in 90% and 9% of NS cases, respec-
tively.17 In children who developed nodding episodes during EEG
Accepted for publication March 1, 2019.
Global Child Health Group, Department of Paediatrics and Department of
Global Health, Academic Medical Center, University of Amsterdam, The
Netherlands.
Address for correspondence: Michaël Boele van Hensbroek, MD, PhD, Depart-
ment of Global Health, Emma Children’s Hospital, Academic Medical
Centre, University of Amsterdam, Amsterdam, The Netherlands. E-mail:
mbvh04@gmail.com.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Hot topics from the oxford infection and immunity in children course
ISSN: 0891-3668/19/3806-0S67
DOI: 10.1097/INF.0000000000002327
Nodding Syndrome: The Unresolved Mystery of a Pediatric
Disease in Sub-Saharan Africa
Gasim Abd-Elfarag, MD and Michaël Boele van Hensbroek, MD, PhD
XXX

Abd-Elfarag et al The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019
S68 | www.pidj.com © 2019 Wolters Kluwer Health, Inc. All rights reserved.
recordings, evidence of atonic seizure was shown by the presence
of electrodecrement and paraspinal electromyographic dropout.10
This high percentage of EEG abnormalities are used by clini-
cians who believe that NS is a form of epilepsy to make their
case. Others argue that using history and clinical examination,
NS cases can easily be distinguished from (pure) epilepsy with-
out nodding episodes.
Magnetic resonance imaging (MRI) studies of the brain of
NS cases show evidence of gliotic changes and cortical and cer-
ebellar atrophy.17,25 The cortical atrophy is more prominent in the
occipital lobe and the parieto-occipital areas of the brain, when
compared with the anterior lobe. In addition, evidence of cerebel-
lar atrophy was shown in most of the NS cases, but with varying
degrees.17 The MRI was unable to detect any focal changes in the
cerebral cortex or the hippocampus.17
ETIOLOGY AND PATHOGENESIS
The etiology of NS remains unknown, and the pathogenesis
has not been clarified. Previous studies have looked into possible
infectious causes, nutritional deficiencies, exposure to toxins and
the possibility of underlying genetic or autoimmune disorders.
Infections
With respect to infectious etiologies, Onchocerca volvulus
(OV), a filarial nematode parasite causing onchocerciasis (river
blindness) has been associated with NS. Four case–control studies
(120 cases and 119 controls in total) conducted in South Sudan and
using skin snip to diagnose OV infection found it in around 86% of
NS cases compared with 48% of controls.13,21 These findings were
in line with findings from Uganda (Table 2). Despite the association
between OV and NS, it remains unclear how an OV infection could
lead to NS. OV is not known to be neuroinvasive but causes river
blindness by eliciting a secondary inflammatory response to some
of its antigens.26–29 Furthermore, there were no reports of NS before
1960, while OV has been around for thousands of years, has no age
restrictions and exists in many other parts of Africa where NS has
never been reported.30 On the other hand, there have been argu-
ments brought forward in favor of a link between OV and NS: (1)
The OV strain found in NS endemic areas may have become more
virulent (neuroinvasive) over time, (2) it may not be OV, but another
as yet unidentified pathogens (eg, a neurotropic virus) transmitted
by the same vector (black fly) that is responsible as OV and (3)
presence of other cross-reacting filarial species, which may only be
found in NS-endemic areas, may cause NS but not in other oncho-
cerciasis endemic areas.
Mansonella perstans (MP), also a vector-borne human filar-
ial nematode, was also found to be associated with NS in a case–
control study conducted in South Sudan (69 cases and 65 controls)
with an OR 3.2 (P value 0.005; Table 2).16 However, the possible
causal link between NS and MP infection has also been disputed
with similar arguments. First, MP infection occurs in other parts
of the sub-Saharan Africa with no reported cases of NS, and sec-
ond, low prevalence of MP was observed in an NS endemic area in
Uganda.31,32
Measles is the third infection that has been associated with
NS in the past, mainly because it is known to be able to cause
severe neurologic disease (subacute sclerosing panencephalitis)
years after the primary measles infection. Three case–control stud-
ies have studied a possible association between having had measles
and NS. The first study found a significant positive association, but
the second found the opposite and the third no association with
reported history of measles infection.15,16,19
With respect to other infections, no associations were found
between NS and other filarial worms (Loa loa and Wuchereria ban-
crofti), neither with trypanosomiasis (sleeping sickness), cysticer-
cosis, hepatitis E or prion disease (eating monkey meat).15,16
Nutrition and toxins
With respect to nutritional factors, an association was found
between NS and vitamin B6 deficiency (OR 7.2; P value 0.001)
and high plasma levels of 3-hydroxykynurenine (OR 4.5; P value
0.013).33 However, these associations could not be confirmed in
another study, with vitamin B6 deficiency almost equally prevalent
in both cases (84%) and controls (75%).15 In looking at the possible
vitamin B6 associations, it is important to note that the known neu-
rologic manifestations of vitamin B6 deficiency are different from
the clinical presentation of NS.
TABLE 1. Nodding Syndrome Consensus Case
Definition
Suspected case: Reported head nodding in a previously healthy
person. Head nodding is defined as repetitive, involuntary drops
of the head to the chest on two or more occasions.
Probable case: Suspected case, with at least 2 major and 1 minor
criteria
Major criteria:
• Head nodding with a frequency of 5–20 times/min
• Age between 3 and 18 years old at onset of nodding
Minor criteria:
• Other neurologic abnormalities (cognitive decline, school
dropout due to cognitive/ behavioral problems, other seizures or
neurologic abnormalities)
• Clustering in space or time with similar cases
• Triggering by food and/or cold weather
• Stunting or wasting
• Delayed sexual or physical development
• Psychiatric manifestations
Confirmed case: Probable case, with documented head nodding
episodes, which is:
• Observed by a trained health care worker, or
• Videotaped head nodding episode, or
• EEG/EMG documenting head nodding as atonic seizure
TABLE 2. Infectious Organisms in Nodding Syndrome Cases and Controls
Infectious Location Cases Controls Odds
P Value StudyOrganism Country Area (yr) # % # % Ratio
Onchocerca volvulus South Sudan Lui (2001) 39 89.7 31 48.3 9.2 0.00003 Spencer PS et al 2013
Amadi (2001) 30 96.7 34 50.0 29.0 — Tumwine JK et al 2012
Lui (2002) 13 92.3 16 43.7 15.4 0.008 Spencer PS et al 2013
Maridi & Witto (2011) 38 76.3 38 47.4 3.2 0.02 CDC 2012
Uganda — 45 71.1 39 53.9 2.11 — Foltz JL et al 2013
Mansonella perstans South Sudan Lui (2001) 39 41.0 31 9.6 3.2 0.005 Spencer PS et al 2013
Amadi (2001) 30 66.6 34 50.0 3.2 0.005 Spencer PS et al 2013

The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019 Nodding Syndrome
© 2019 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | S69
One study showed associations between NS and various
food-related factors, including consumption of moldy maize (OR
4.3; P value 0.009), emergency food (OR 4.0; P value 0.016) and
red/brown sorghum (OR 6.2; P value 0.049).19 However, the rel-
evance of these findings is debatable because all of these foods have
been consumed in many other African (and Asian) countries, with-
out reported cases of NS.34
There were no associations found between NS and con-
sumption of agricultural seeds, insects, rodent and baboon brains,
bush meat and cassava.15 Also, no associations were detected
between NS or other nutritional deficiencies (vitamin A, B12,
folate, zinc, selenium) and with other toxic substances (cop-
per, mercury).15 Although a study in Kitgum district, Uganda,
has identified an association between NS and the use of plant
roots for traditional medicines,15 this association could not be
confirmed in another study in a similar area.19 Furthermore, the
study that found the association could not identify the plant spe-
cies responsible for this association, and many different plant
species are used as traditional medicines in Uganda and many
other countries across the globe. The plant roots might have
also been consumed as a traditional treatment for NS rather than
being the cause of NS.
Exposure to toxic substances found in biologic or chemical
weapons was also found to be associated with NS among Ugandan
children15; however, this finding could not be confirmed in studies
among South Sudanese NS cases.16,21
Autoimmunity
An autoimmune reaction elicited by an OV infection has also
been suggested as the etiology of NS. In vitro studies have shown
that antibodies to leomedin-1, normally expressed on brain cells,
cross-reacts with OV proteins and that autoantibodies to leomedin-1
are considered neurotoxic.27 When compared with village controls,
autoantibodies to leomedin-1 were detected in the serum and CSF
of 53% NS cases and in 31% controls (OR 2.7; P value 0.024).27
Outstanding questions to be investigated include why only half of
NS cases were found to have autoantibodies and how to explain that
a third of healthy controls have the same putatively highly neuro-
toxic autoantibodies. In contrast, although an association has been
found between autoantibodies against N-methyl-D-aspartic acid
receptor and against voltage-gated potassium channel complex and
epilepsy and encephalitis,35,36 no association was found between
these autoantibodies and NS,37 neither was any epilepsy specific or
any consistent rare variant genes associated with NS found.1
Pathogenesis
Autopsy studies on the brains of 5 Ugandan NS children
showed evidence of neurodegenerative changes, suggesting NS
could be a new form of tauopathy.38 In favor of this hypothesis
tau-immunoreactive neuronal neurofibrillary tangles, pretangles
and neuropil threads and dot-like tau were found in the cerebral
cortex, brainstem and basal ganglia of the 5 fatal NS cases.38
However, the distribution and cellular histopathology in NS is not
comparable to other known tauopathies, and it remains unclear
whether the neurodegenerative pathologic changes found in the
brains of the NS children are the cause or a consequence of the
seizure activity. The number of cases included in the autopsy
study is too small to draw strong conclusions but do emphasize
the need for a larger series. However, this is very difficult to
organize because most children with NS will die in very remote
areas, unexpectedly, often because of drowning or falling into fire,
and furthermore, most families are likely to reject a request for an
autopsy because of cultural reasons.
TREATMENT AND OUTCOME
There is no curative treatment available for NS. The focus,
therefore, is currently on optimal management of the syndrome.
This would ideally be a package of intervention, including pro-
phylactic anticonvulsants, nutritional treatment and supplementa-
tions, physiotherapy, counseling and psychosocial support for the
affected children and their families. The aim of this package is to
reduce the frequency of nodding episodes and other seizures and
to improve the nutritional status and school attendance. Anticon-
vulsants (carbamazepine, phenobarbitone, phenytoin and sodium
valproate) have been shown to be able to achieve complete seizure
control in 25% and to reduce seizure frequency in over 70% of
NS cases. Furthermore, anticonvulsive treatment improves behav-
ior, independence and school attendance in 59%, 80% and 40%,
respectively.39 It is thought that anticonvulsants may also reduce the
incidence of death from continuous seizures, severe burns (fall in
fires) and drowning, but it is unknown whether it also halts disease
progression.
Based on the assumption that OV infection is the cause of
NS, people have suggested using the control of OV as potentially
presumptive NS treatment. There are plans to roll out and improve
existing programs of community treatment with ivermectin and
onchocerciasis vector control. It has also been proposed to apply
another OV-based approach by adding doxycycline to the NS
treatment package. Doxycycline kills the Wolbachia bacteria,
which live in symbiosis with the adult OV worm. It is thought that
killing them may elicit premature death of the OV adult worm.40
However, doxycycline is contraindicated in children younger than
8 years of age, below which many children are already affected
by NS.
SOCIOECONOMIC BURDEN AND COMMUNITY
PERCEPTION
The socioeconomic burden of NS is for a large part caused
by the community perception of the disease. Psychophysical dis-
ability caused by NS often leads to individual and family stigma,
social isolation and a compromised livelihood.41–43 Mentally
retarded NS girls are frequently exposed to sexual abuse. NS
children often drop out of school because of the severity of their
illness, discrimination and from fear in the community that the
disease may be contagious.41–44 Furthermore, there is a range of
beliefs in these communities about the etiology of NS, which
include, not only infection, but also chemicals from munitions,
expired/poisoned food aid and evil spirits and curses.41,43–45 Most
care takers initially seek healthcare for their affected children
from formal health facilities, but when clinical improvement is not
achieved, will often try alternative medicines or consult witch doc-
tors. This also often ends in a disappointment. NS also has a big
economic impact on these already impoverished families, because
parents/guardians tend to devote most of their time attending to
their affected children instead of going to the farm or performing
other income-generating activities.
POSSIBLE APPROACHES TO FURTHER
RESEARCH
Despite the investigations done so far in a limited num-
ber of children with NS in the 3 affected countries, there remain
major knowledge gaps. First, future research should focus on the
unknown etiology and pathogenesis of NS. Second, questions
regarding NS prevalence, incidence, long-term outcome and risk
assessment need to be urgently addressed to permit assessment of
the disease burden and initiation of timely support for rehabilitation
of the affected children and their families.

Abd-Elfarag et al The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019
S70 | www.pidj.com © 2019 Wolters Kluwer Health, Inc. All rights reserved.
The South Sudan Nodding Syndrome Study, currently in
progress, aims to address the most critical outstanding questions.
In the first component of the study, the size of the NS problem is
being determined through a community-based survey in a restricted
highly affected area (Western Equatoria State, South Sudan). This
will provide insight into the prevalence of NS, clustering of cases
and association with possible etiologic risk factors (black fly breed-
ing sites, types of food consumption, etc). In addition, by repeat-
ing the survey every 12 months, the study will provide informa-
tion about the incidence, natural history and risk factors for NS
disease progression. The second component is a two-phase etiol-
ogy study with a case–control design. Phase 1 focuses mainly on
infectious etiology using next-generation sequencing (VIDISCA)
to identify known and novel pathogens in the CSF of NS cases and
gene expression profiling in white blood cells of cases and con-
trols to study the host response. If phase 1 fails to identify a cause,
a large-scale case–control study with broad screening of toxic,
autoimmune, metabolic and other potential etiologic factors will
be started. This study will contribute to resolving the mystery, but
other studies focusing on social and economic impact and initia-
tives to develop social support programs for the affected children,
their families and communities are urgently needed.
Although, the impact of NS is confined to specific areas
within a few east African countries, the etiologic mystery is remi-
niscent of the puzzle in the 1980s surrounding slim disease in the
same region of Africa.
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