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

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

Gasim Abd-Elfarag, MD and Michaël Boele van Hensbroek, MD, PhD

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

The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019 www.pidj.com | S67 Abd-Elfarag et al The Pediatric Infectious Disease Journal • Volume 38, Number 6S, June 2019

recordings, evidence of atonic seizure was shown by the presence (120 cases and 119 controls in total) conducted in South Sudan and of electrodecrement and paraspinal electromyographic dropout.10 using skin snip to diagnose OV infection found it in around 86% of This high percentage of EEG abnormalities are used by clini- NS cases compared with 48% of controls.13,21 These findings were cians who believe that NS is a form of epilepsy to make their in line with findings from Uganda (Table 2). Despite the association case. Others argue that using history and clinical examination, between OV and NS, it remains unclear how an OV infection could NS cases can easily be distinguished from (pure) epilepsy with- lead to NS. OV is not known to be neuroinvasive but causes river out nodding episodes. blindness by eliciting a secondary inflammatory response to some Magnetic resonance imaging (MRI) studies of the brain of of its antigens.26–29 Furthermore, there were no reports of NS before NS cases show evidence of gliotic changes and cortical and cer- 1960, while OV has been around for thousands of years, has no age ebellar atrophy.17,25 The cortical atrophy is more prominent in the restrictions and exists in many other parts of Africa where NS has occipital lobe and the parieto-occipital areas of the brain, when never been reported.30 On the other hand, there have been argu- compared with the anterior lobe. In addition, evidence of cerebel- ments brought forward in favor of a link between OV and NS: (1) lar atrophy was shown in most of the NS cases, but with varying The OV strain found in NS endemic areas may have become more degrees.17 The MRI was unable to detect any focal changes in the virulent (neuroinvasive) over time, (2) it may not be OV, but another cerebral cortex or the hippocampus.17 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 ETIOLOGY AND PATHOGENESIS found in NS-endemic areas, may cause NS but not in other oncho- The etiology of NS remains unknown, and the pathogenesis cerciasis endemic areas. has not been clarified. Previous studies have looked into possible Mansonella perstans (MP), also a vector-borne human filar- infectious causes, nutritional deficiencies, exposure to toxins and ial nematode, was also found to be associated with NS in a case– the possibility of underlying genetic or autoimmune disorders. 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 Infections causal link between NS and MP infection has also been disputed With respect to infectious etiologies, Onchocerca volvulus with similar arguments. First, MP infection occurs in other parts (OV), a filarial nematode parasite causing onchocerciasis (river of the sub-Saharan Africa with no reported cases of NS, and sec- blindness) has been associated with NS. Four case–control studies 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 TABLE 1. Nodding Syndrome Consensus Case NS in the past, mainly because it is known to be able to cause Definition severe neurologic disease (subacute sclerosing panencephalitis) years after the primary measles infection. Three case–control stud- Suspected case: Reported head nodding in a previously healthy ies have studied a possible association between having had measles person. Head nodding is defined as repetitive, involuntary drops and NS. The first study found a significant positive association, but of the head to the chest on two or more occasions. the second found the opposite and the third no association with Probable case: Suspected case, with at least 2 major and 1 minor reported history of measles infection.15,16,19 criteria Major criteria: With respect to other infections, no associations were found • Head nodding with a frequency of 5–20 times/min between NS and other filarial worms (Loa loa and Wuchereria ban- • Age between 3 and 18 years old at onset of nodding crofti), neither with trypanosomiasis (sleeping sickness), cysticer- Minor criteria: cosis, hepatitis E or prion disease (eating monkey meat).15,16 • Other neurologic abnormalities (cognitive decline, school dropout due to cognitive/ behavioral problems, other seizures or neurologic abnormalities) Nutrition and toxins • Clustering in space or time with similar cases With respect to nutritional factors, an association was found • Triggering by food and/or cold weather between NS and vitamin B6 deficiency (OR 7.2;P value 0.001) • Stunting or wasting and high plasma levels of 3-hydroxykynurenine (OR 4.5; P value • Delayed sexual or physical development 0.013).33 However, these associations could not be confirmed in • Psychiatric manifestations Confirmed case: Probable case, with documented head nodding another study, with vitamin B6 deficiency almost equally prevalent episodes, which is: in both cases (84%) and controls (75%).15 In looking at the possible • Observed by a trained health care worker, or vitamin B6 associations, it is important to note that the known neu- • Videotaped head nodding episode, or rologic manifestations of vitamin B6 deficiency are different from • EEG/EMG documenting head nodding as atonic seizure the clinical presentation of NS.

TABLE 2. Infectious Organisms in Nodding Syndrome Cases and Controls

Infectious Location Cases Controls Odds

Organism Country Area (yr) # % # % Ratio P Value Study

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

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

The South Sudan Nodding Syndrome Study, currently in 16. Spencer PS, Vandemaele K, Richer M, et al. Nodding syndrome in Mundri progress, aims to address the most critical outstanding questions. county, South Sudan: environmental, nutritional and infectious factors. Afr Health Sci. 2013;13:183–204. In the first component of the study, the size of the NS problem is 17. Idro R, Opoka RO, Aanyu HT, et al. Nodding syndrome in Ugandan chil- being determined through a community-based survey in a restricted dren—clinical features, brain imaging and complications: a case series. highly affected area (Western Equatoria State, South Sudan). This BMJ Open. 2013;2013:e002540. will provide insight into the prevalence of NS, clustering of cases 18. Winkler AS, Friedrich K, König R, et al. The head nodding syndrome–clin- and association with possible etiologic risk factors (black fly breed- ical classification and possible causes. Epilepsia. 2008;49:2008–2015. ing sites, types of food consumption, etc). In addition, by repeat- 19. Spencer PS, Mazumder R, Palmer VS, et al; other Members of the Oregon- ing the survey every 12 months, the study will provide informa- Uganda Nodding Syndrome Research Team. Environmental, dietary and tion about the incidence, natural history and risk factors for NS case-control study of Nodding Syndrome in Uganda: a post-measles brain disease progression. The second component is a two-phase etiol- disorder triggered by malnutrition? J Neurol Sci. 2016;369:191–203. ogy study with a case–control design. Phase 1 focuses mainly on 20. Piloya-Were T, Odongkara-Mpora B, Namusoke H, et al. Physical growth, puberty and hormones in adolescents with Nodding Syndrome; a pilot infectious etiology using next-generation sequencing (VIDISCA) study. BMC Res Notes. 2014;7:858. to identify known and novel pathogens in the CSF of NS cases and 21. Centers for Disease Control and Prevention. 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