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International Journal of Infectious Diseases 17 (2013) e149–e152

Contents lists available at SciVerse ScienceDirect

International Journal of Infectious Diseases

jou rnal homepage: www.elsevier.com/locate/ijid

Review

Reviewing the evidence on nodding syndrome, a mysterious tropical disorder

Danie¨l Arnoldus Korevaar *, Benjamin Jelle Visser

Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands

A R T I C L E I N F O S U M M A R Y

Article history: Objectives: To review the literature on the prevalence, clinical manifestations, pathogenesis, treatment,

Received 3 June 2012

and implications of nodding syndrome (NS).

Received in revised form 11 August 2012

Methods: This is a narrative review.

Accepted 26 September 2012

Results: NS is a mysterious tropical disorder that is emerging in South Sudan, southern Tanzania, and

Corresponding Editor: William Cameron,

northern Uganda. Over the past decade, thousands of children have become affected, but the prevalence

Ottawa, Canada

is unknown. NS is characterized by an occasional nodding of the head, which is considered as a form of

epilepsy. After symptoms appear, the patient’s health rapidly deteriorates. Seizures, stunted growth, and

Keywords: mental retardation may appear. In endemic areas, NS is increasingly becoming a public health problem

Head nodding disease

with high morbidity and mortality, and severe social, psychological, and economic implications.

Nodding syndrome

However, the pathogenesis is unknown. Evidence suggests a role for Onchocerca volvulus, the parasitic

Onchocerca volvulus

ﬁlarial worm responsible for river blindness, which is highly endemic in these areas. There is no cure for

Onchocerciasis

NS, and treatment is symptomatic with common anticonvulsants to improve the quality of life.

River blindness

Conclusions: NS seems to be a rapidly growing problem in several eastern African countries. Although it

is starting to receive more and more attention in the scientiﬁc literature, little is known about NS. A

better understanding of the pathogenesis may lead to prevention and treatment opportunities.

1. Introduction condition was ﬁrst observed in 2003, seems to be the next most

important epicenter. In late 2009, the Ministry of Health of Uganda

In 1962, Louise Jilek-Aall, a Norwegian physician, described a reported that more than 2000 children were affected in northern

mysterious disorder characterized by head nodding in several Uganda. In 2011, the disorder started to receive more and more

children in southern Tanzania. Some of these children eventually attention in journals and the scientiﬁc literature. Several reports

developed tonic–clonic seizures. In 1983, head nodding was also stated that large areas of northern Uganda were experiencing an

described among several patients in Liberia. For years, the outbreak of the condition, with more than 1000 cases being

disorder remained isolated in these areas. However, around diagnosed between August and mid-December of that year. Further

1990, physicians began observing a similar disorder in distinct outbreaks were reported in early 2012, with the disease now

3,4

areas in southern Sudan (currently known as South Sudan). After spreading between districts in northern Uganda, leaving at least 170

this, several cases of ‘head nodding’ were also observed in western patients dead and 3000 to 5000 others nodding continuously in

5 9–11

Uganda. The condition was ofﬁcially reported to the World Health these areas. However, the exact prevalence and geographic

Organization (WHO) by Warren Cooper, a missionary doctor, from distribution of the disease in the affected countries is unknown. In

southern Sudan in 1997 and first described in the scientific August 2012, at the first International Scientific Meeting on Nodding

3,4

literature as ‘nodding disease’ in 2003. Syndrome, a consensus was reached to refer to the combination of

Over the last decade, the disorder has appeared to be a rapidly signs and symptoms as ‘nodding syndrome’.

growing problem in several eastern Sub-Saharan African countries.

Increasing numbers of cases have been reported in geographically

2. Clinical features and classiﬁcation

localized areas of southern Sudan, southern Tanzania, and

northern Uganda. In 2003, an estimated 300 cases were reported

6 Nodding syndrome mainly affects children and adolescents.

in southern Sudan, but currently, the disorder is affecting

7 The WHO reported that 54% of patients are male. Although it is

thousands of children in this area. Northern Uganda, where the

uncertain whether there exists one deﬁned clinical condition that

can be applied in all reported areas, all current news reports and

* Corresponding author. Tel.: +31 64 2993008. scientiﬁc publications more or less agree on the clinical course. The

E-mail address: [email protected] (D.A. Korevaar). ﬁrst stage of the disorder is characterized by an occasional,

e150 D.A. Korevaar, B.J. Visser / International Journal of Infectious Diseases 17 (2013) e149–e152

momentary, involuntary nodding of the head. The frequency of but so far they have had little success in elucidating the

the nodding differs among patients. In a study group of 62 patients, pathogenesis. It was hypothesized that the disorder may be

more than half of them had daily episodes of head nodding. It is caused by toxic residues of the biological and chemical weapons

suggested that the nodding is caused by a brief loss of neck muscle left over from the civil war in southern Sudan. Or that it is linked to

7,14

tone that may be due to abnormal brain activity. Several eating the donated seeds coated with toxic chemicals that were

16 6

publications have reported that the nodding is provoked by eating, meant for planting, or to eating monkey meat. However, after

5,16

and sometimes cold weather. However, the signiﬁcance of investigation, the WHO teams ruled out involvement of an

14 3

these signs is unclear. Cases have been described where the environmental pollutant, chemical agent, or food toxins. Parasi-

nodding is associated with staring spells or a short loss of muscle tological examinations established that the disorder is not caused

tone of the upper extremities, and loss of consciousness may by infection with Trypanosoma brucei gambiense, Wuchereria

14 3

occur. Before the nodding ﬁrst appears, most children are bancrofti, or Loa loa. In addition, CDC teams have so far not been

considered normal. However, once symptoms manifest, the able to link any changes in dietary or cultural practices to the

patient’s health seems to deteriorate rapidly. First the nodding syndrome. However, there might be a connection between

becomes more frequent and longer-lasting. Later on, tonic–clonic nodding syndrome and infection with Onchocerca volvulus. This

or psychomotor seizure episodes may develop, often leading to parasitic ﬁlarial nematode is transmitted by the black ﬂy (Simulium

collapse and injuries. Documented natural history studies are species) and is responsible for river blindness, or onchocerciasis

19–21

lacking and little is known about the short- and long-term (see Appendix 1 ). Interestingly, nearly all patients affected

outcomes, but over time, many children become severely weak with nodding syndrome are thought to live near permanent fast-

14 9

and stunted growth sets in. In addition, many decline cognitively, moving streams, the breeding habitat of the black ﬂy. In addition,

which eventually may lead to mental retardation. In the same in the latter half of 2009, an upsurge of onchocerciasis infection

study, over 40% of the 62 patients seemed to have cognitive rates was recorded in parts of northern Uganda, the same parts as

impairment, with half of them affected severely. Children lose where the sudden increase in nodding syndrome cases was

their attention span and their ability to interact normally. described during that period. Furthermore, it was observed that

Furthermore, many suffer from malnutrition because they are 93% of surveyed patients in southern Sudan were infected with O.

unable to feed themselves, partly because of the cognitive volvulus, compared to 63% among children without the disor-

7 6,14

impairment and partly because the seizures inhibit eating. der. However, although these data have been reported in

Eventually, some patients die, often as a result of uncontrolled several reports, any further information on this study, for example

3,7,9

seizures that may lead to traumata, drowning, or burning. No the number of patients involved, is lacking. Nevertheless, more

child is known to have recovered from the syndrome, and it is recent preliminary results of an investigation supported by the

unknown whether it is communicable. However, the WHO WHO in southern Sudan show that 75% of the 52 patients with

reported recently that investigations have revealed the disorder nodding syndrome had a positive skin snip for O. volvulus,

8 23

not to be transmissible from person to person. compared to 47% among 38 healthy children. In a case–control

Although nodding syndrome causes high morbidity and study performed in 2011, CDC investigators found that in one

mortality in endemic areas, the disorder is still poorly understood South Sudanese community, 88% of 25 patients had positive skin

and information on the syndrome is scarce. There is a wide variety samples for the parasitic infection, compared to 44% of 25 healthy

of manifestations between patients and, therefore, it is sometimes controls. However, they failed to ﬁnd any difference in a second

uncertain whether people are describing the same phenome- village, with around half of the 13 patients and half of the 13

14,18

non. For example, it was reported that some patients initially controls being infected. Results from CDC investigators in Uganda

presented with generalized seizures instead of nodding. Cur- have not been published, but it has been reported that these also

rently, there is one clinical classiﬁcation available, subdividing the found a positive association between the worm and the

symptoms into ‘head nodding only’ or ‘head nodding plus’, the syndrome.

latter consisting of additional partial or generalized non-head These observations appear meaningful, since O. volvulus has

nodding epileptic seizures. been associated with epilepsy before. For example, in 1992, an

unusually high number of patients with epilepsy were observed in

3. Pathophysiology a rural area of western Uganda, where infection with O. volvulus is

hyperendemic. In addition, onchocerciasis has been associated

The initial nodding that characterizes the syndrome is generally with the ‘Nakalanga syndrome’, which has many similarities with

considered as a form of epilepsy. This is not unexpected since head nodding syndrome. This syndrome consists of epilepsy, stunted

nodding as a symptom has been associated with various epilepsy growth, and mental retardation and has been reported from

14 25 26

syndromes. In 2002, electroencephalographs (EEGs) on 31 Uganda and Burundi. In 2004, a meta-analysis of all available

patients with nodding syndrome performed by a neurologist epidemiological studies on the relationship between O. volvulus

recruited by the WHO in southern Sudan were all abnormal and and epilepsy was only able to demonstrate a nearly signiﬁcant

3,16 27

showed speciﬁc progressive epileptic encephalopathy. EEGs association. However, a more recent meta-analysis of epidemio-

between nodding episodes on 10 patients in southern Tanzania logical studies found that for every 10% increase in the prevalence

showed an abnormal background in six of them, of whom two had of onchocerciasis, epilepsy rates go up by 0.4%.

interictal epileptic activity. However, the authors were unable to Several mechanisms have been proposed to explain the

determine whether the seizures were focal or generalized in relationship between epilepsy and onchocerciasis. O. volvulus

nature. The assumption that nodding syndrome may be a seizure may be present in the central nervous system. Microﬁlariae have in

disorder is strengthened by the fact that many patients who start fact been demonstrated in the cerebrospinal ﬂuid (CSF) of

treatment with anticonvulsants have a signiﬁcant reduction in onchocerciasis patients. Another possibility involves immuno-

15,16

seizure frequency. logical mechanisms. Modulators and cytokines involved in the

The cause of nodding syndrome as observed in South Sudan, immunological response to the parasite may induce changes in

Tanzania, and Uganda is unclear. In the past decade, the WHO and cerebral activity. Finally, there might be a triggering role of

the US Centers for Disease Control and Prevention (CDC) have sent insomnia due to itching. Several studies have shown a marked

several teams of experts to endemic areas to investigate the activation of epileptiform abnormalities and triggering of seizures

disorder. Many possible causes have been explored by these teams, following sleep deprivation.

D.A. Korevaar, B.J. Visser / International Journal of Infectious Diseases 17 (2013) e149–e152 e151

In 2008, the ﬁrst prospective study to date was performed in capacity to deal with this emerging medical threat. Assistance

southern Tanzania and found that 84% of the 51 children affected from the international community may be necessary.

with nodding syndrome carried the parasite. However, invasion

into the central nervous system could not be demonstrated since

5. Conclusions and recommendations

only three of 48 patients had elevated levels of anti-worm immune

cells in their CSF samples. Nevertheless, it is unknown whether

Nodding syndrome is an unusual tropical disorder that seems to

these patients had used antiﬁlarial medication. Perhaps micro-

32 be rapidly spreading among geographically localized areas in South

ﬁlariae were present in the CSF before treatment. An autoim-

Sudan, southern Tanzania, and northern Uganda. The syndrome

mune mechanism was not investigated and could therefore not be

appears consistent with epilepsy but with a stereotypic presenta-

excluded in this study.

tion, and there might be an association with the ﬁlarial nematode

Potentially contradicting the possibility of the involvement of O.

Onchocerca volvulus. In the endemic areas, nodding syndrome is

volvulus in the pathogenesis of nodding syndrome is that people

increasingly becoming a considerable public health problem with

living in other areas where onchocerciasis is endemic are not

7 high morbidity and mortality, and possibly severe social, psycho-

affected by nodding syndrome. However, there are also geo-

logical, and economic implications. However, currently little is

graphical differences in the severity of other symptoms among

known about its prevalence, pathogenesis, and treatment. Further

onchocerciasis patients, for example, ocular lesions. It has been

research is necessary. To date, besides several investigations carried

proposed that this might be explained by the fact that the

out by international teams provided by the World Health

microﬁlariae of some O. volvulus strains are located more deeply in

29 Organization (WHO) and the US Centers for Disease Control and

the dermis than those of other strains. These ‘strain-dependent’

Prevention (CDC), only one prospective study among patients has

manifestations might also exist for nodding syndrome. Neverthe- 14

been published. A better understanding of the pathogenesis may

less, onchocerciasis has been prevalent in many African countries

lead to prevention and treatment opportunities. Researchers should

for a very long time and, therefore, its involvement in the current

work closely with local ministries of health, the WHO, and the CDC in

outbreak of nodding syndrome does not explain why there have

addressing this syndrome. Cohorts should be longitudinally

not been any outbreaks before.

compared in terms of clinical presentation and possible etiological

Besides this parasite hypothesis, there are other possible

factors between different countries. An effective control and

pathogenic mechanisms. An interesting ﬁnding is that magnetic

surveillance program is a necessity and should be implemented

resonance imaging (MRI) in 12 cases showed hippocampus

14 to monitor the prevalence of the syndrome, its clinical manifesta-

pathologies in ﬁve patients and gliotic changes in ﬁve patients.

tions, and its geographic distribution. Geographic information

Furthermore, familial clustering may be present, since 84% of 62

14 systems (GIS) could be used to monitor the emergence of the

patients had at least one relative with epilepsy. The WHO

syndrome, both spatially and in time. This could aid decision-

reported that most of the affected children suffer a deﬁciency of

making and contribute to the proper allocation of resources. So far,

vitamin B6 (pyridoxine) and other micronutrients such as vitamin

33 no (published) post-mortem studies have been performed. Such

A, selenium, and zinc. This is currently also being investigated by

7,17 studies might be beneﬁcial in obtaining a better insight into the

a CDC team. Some epidemiologists have suggested that climate

pathogenesis. Randomized controlled trials should be performed to

change may have played a part in the emergence of the syndrome,

9 assess the effectiveness of proposed treatments. Because of the

especially if it could be deﬁnitively linked to O. volvulus.

assumed relationship with the black ﬂy-borne parasite O. volvulus,

mass treatment with ivermectin, a broad-spectrum antiparasitic

4. Therapy and impact

agent, should be reinforced in endemic areas. Furthermore, local

health workers should be trained in the identiﬁcation of the

As the cause of nodding syndrome has not yet been identiﬁed,

syndrome and how to support patients psychologically and socially.

there is no known cure. Treatment with common anticonvulsants

Ideally, anticonvulsant drugs should become easily accessible to

seems to control the symptoms in some patients. According to

improve the quality of life and life-expectancy of patients. However,

health workers, patients who start treatment early and on a regular

in reality this may be hard to achieve since the epilepsy treatment

basis have seizures less frequently and, therefore, fewer complica-

16 gap, the number of people with active epilepsy who are not being

tions. A study has shown that treatment led to, on average, a 50%

15 appropriately treated, is gigantic in most developing countries. In

reduction in seizure frequency. The administration of anti-

2010, a systematic review of population-based studies of epilepsy

epileptic drugs to patients whose seizures were responsive to such

23 prevalence demonstrated that this treatment gap was over 75% in

medication was recommended by a WHO team. However, even

low-income countries, compared to gaps of less than 10% in many

without deﬁnitive evidence of the cause of the syndrome, the CDC 37

high-income countries. As for Uganda and Tanzania, published

intends to perform interventional drug trials assessing the 38–40

reports have demonstrated treatment gaps close to 100%.

effectiveness of standard anticonvulsants as well as high doses

18 Therefore, interventions to ﬁght nodding syndrome containing

of vitamin B6.

elements of epilepsy treatment are likely to have a limited impact.

Nodding syndrome is devastating to patients and communities.

Even worse, it might damage the overall efﬁciency of a program if the

As it progresses, many patients become malnourished and

9 respective resources are deducted from other actions with better

completely dependent on their caregivers. Access to education

prospects.

and standard of performance in school is low among those

15 Conﬂict of interest: We declare no conﬂict of interest.

affected. In addition, some are isolated because of the fear of

contagion. Several studies have shown that, in rural tropical areas,

epilepsy in general has enormous demographic and sociocultural

consequences, such as stigmatization, shorter school attendance, Appendix 1

34–36

decreased marriage and fecundity rates, and high mortality.

Currently, many local health workers are unfamiliar with NS and Onchocerciasis

do not know how to treat patients. In addition, antiepileptic

drugs are often unavailable in the affected areas. This is a Onchocerciasis, or river blindness, is caused by the parasitic

particular worry in South Sudan, which achieved political ﬁlarial nematode Onchocerca volvulus. The disease mainly

independence only recently and may therefore have a limited affects people living near fast-ﬂowing rivers and is a major

e152 D.A. Korevaar, B.J. Visser / International Journal of Infectious Diseases 17 (2013) e149–e152

13. Nodding syndrome meeting, researchers agree on case deﬁnition and establish

cause of blindness and skin disease. To date, the majority of

research agenda. World Health Organization, Regional Ofﬁce for Africa. Avail-

infections have occurred in Sub-Saharan Africa, but cases have

able at: http://www.afro.who.int/en/uganda/press-materials/item/4826-nod-

also been reported in Yemen and areas of Central and South ding-syndrome-meeting-researchers-agree-on-case-deﬁnition-and-establish-

research-agenda.html (accessed August 11, 2012).

America. Overall, 120 million people live in areas of risk and

14. Winkler AS, Friedrich K, Ko¨nig R, Meindl M, Helbok R, Unterberger I, et al. The

37 million people are affected worldwide, with more than 99%

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