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Map of Uganda showing Kitgum District; the approximate location of Tumangu Village is marked with a spot. The capital city of Kampala (box) is ~8 h by road from Kitgum, which abuts South Sudan.
Source publication
Nodding Syndrome (NS) is an epileptic encephalopathy characterized by involuntary vertical head nodding, other types of seizures, and progressive neurological deficits. The etiology of the east African NS epidemic is unknown. In March 2014, we conducted a case-control study of medical, nutritional and other risk factors associated with NS among chi...
Contexts in source publication
Context 1
... northern Uganda (Acholiland), reports of NS began to appear in 1997 [7,9], with the first recorded cases in Kitgum District in 1998 ( Fig. 1). Cases rapidly increased annually beginning in 2001, with peaks in 2003-2005 and 2008, 5-6 years after peaks in the number of wartime conflicts and deaths. Additionally, peaks of NS followed peak influxes 5-7 years earlier of households into internal displacement camps [9]. The 2013 estimated number of probable Ugandan NS Cases was ...
Context 2
... study was set in Tumangu Village, Lamit Parish, Labongo Akwang Sub-County, Kitgum District in northern Uganda (Fig. 1). An isolated, largely rural community, Kitgum District has high levels of pov- erty, inadequate water and sanitation, and significant disease burden. Child and maternal mortality rates in 2007 were higher than in most parts of Uganda [16]. Between 1987Between and 2006Between /2008, this region was a civil war zone involving the Lords ...
Citations
... (iii) Malnutrition: Vitamin B6 deficiency was found to be a main risk factor for NS [66]. In families with one or more NS cases, a history of shortage and consumption of moldy maize was notably more prevalent before the onset of head nodding [67]. (iv) Genetics: An association was found between NS and both protective HLA haplotype (HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01), and susceptible motif (Ala24, Glu63 and Phe67), in the HLA-B peptide-binding groove. ...
Background/Objectives: Epilepsy is a major public health issue in Sub-Saharan Africa, particularly among children, due to limited healthcare resources, socioeconomic inequalities, and cultural stigma that often result in underdiagnosis and undertreatment. This review examines pediatric epilepsy’s diagnosis, classification, and management in this setting, highlighting the need for culturally appropriate interventions to improve care quality and address these challenges. Methods: A review of the literature was conducted using MEDLINE, Embase, Scopus, and Web of Science databases to identify pertinent studies published between 2013 and 2024. This review included studies examining the epidemiology, seizure classification and etiologies of epilepsy among children in Sub-Saharan Africa. Results: This review revealed higher incidence and prevalence of epilepsy in Sub-Saharan Africa compared to high-income countries, primarily attributable to factors such as infectious diseases, perinatal injuries, and limited diagnostic resources. The most frequently reported types of epilepsy were generalized and focal seizures, with significant etiological contributions from structural and infectious causes, including nodding syndrome and HIV-related epilepsy. The treatment gap remains considerable, with up to 80% of children not receiving appropriate antiseizure medications. Conclusions: The diagnosis and treatment of epilepsy in pediatric populations in Sub-Saharan Africa is complicated by several factors, including cultural stigma and the lack of adequate healthcare infrastructure. There is an urgent need for culturally tailored diagnostic tools, improved access to affordable treatments, and public health initiatives aimed at reducing stigma. Addressing these gaps through enhanced research, improved healthcare access, and targeted educational campaigns is crucial for improving the quality of life for children with epilepsy.
... chronic immune system dysregulation, epigenetic/genetic structural and functional abnormalities [5]. The use of moldy maize was found to be associated with NS in Uganda [6]. Hence, the interaction between aflatoxins B 1 and G 1, MECP2 and malnutrition merits specific attention. ...
... In Tanzania, head nodding among the Pogoro of the central Mahenge Highlands and peripheries was first recorded in 1934 and reported in 1960 [20]; this population was also subject to famine (1939), civil disturbances, community displacement (1943) [21,22] and annual drought periods. In addition to these special environmental factors, a northern Ugandan Acholi community (Kitgum) heavily affected by NS reported that the peak of onset of head nodding occurred among affected children (mostly 5-15 years at onset) in the month of April following the hottest (31-33 • C) and driest period, which spans January-March [23,24]. Thus, NS is a geographically restricted and temporally expressed brain disorder of childhood, primarily if not exclusively of environmental etiology, that has surfaced in impoverished nearequatorial communities subject to internal displacement. ...
... Global acute malnutrition (6.0%) and stunting were higher in the age groups 6-12 months and 13-24 months compared to other age groups [28]. In Kitgum district, families with NS cases (relative to household and community controls) reportedly had been significantly more dependent on emergency food and, immediately prior to head nodding onset in one or more children, subsistence on moldy plant materials, specifically moldy maize [23]. In 1992, water sources in Kitgum included shallow wells, streams, rivers, valley dams, and boreholes, 77.3% of which were not functional [29]; roundtrip walking distance was approximately 2.4 km [29] and, in the dry season, algae grew on the water surface [30,31]. ...
... In two other northern Ugandan IDP camps (Gulu and Amuru), a 2006-2009 study of 1206 respondents found that 70% of people had been displaced for 5 or more years (2-> 10 years), 89.9% lacked sufficient food and water; common illnesses included fever/malaria (48%), respiratory problems (45%), watery or bloody diarrhea (22%), and typhoid and hepatitis E [34][35][36]. Given insufficient water for drinking (52.9%), washing (25.4%), cooking (10.6%), bathing (3.0%) and other uses (6.1%) [18][19][20][21][22][23][24][25], 12.1% of Ugandan respondents relied on unprotected water sources, including wells, ponds, lakes, streams, and rivers [37]. Hot and dry weather stimulates the proliferation of cyanobacteria in freshwater, consumption of which considerably increases the risk of cyanotoxin poisoning [38]. ...
... In addition, no measles virus genetic material was found by PCR in the CSF of either cases or controls [14]. The last study on the subject took place in 2014 and found that a history of measles was ultimately a risk factor for NS [22]. Because of the similarities between NS and subacute sclerosing panencephalitis (SSPE), the authors hypothesized that NS could be a post-measles disorder like SSPE. ...
... Because of the similarities between NS and subacute sclerosing panencephalitis (SSPE), the authors hypothesized that NS could be a post-measles disorder like SSPE. Other viruses such as hepatitis E [14] and varicella virus [22] have been studied but none were associated with NS. No studies on bacterial infections have yet been done in the context of the etiology of NS. ...
... No studies on bacterial infections have yet been done in the context of the etiology of NS. All results are shown in Table 2. Of the three studies dealing with viral infections [13,14,22], two were of good quality according to both the NOS and DCP scale. One article was judged to be of average quality on both scales. ...
Introduction: Nodding Syndrome (NS) remains a poorly understood disorder. For a long time, it has been thought to be restricted to East Africa, however cases in Central Africa have been increasing over time. The objective of this systematic review (SR) was to provide a summary of the state of knowledge on NS to date. Methods: All original articles published on NS up to November 2021 were searched in four major databases and in the grey literature. Commentaries, editorials, book chapters, books, conference paper, qualitative studies that mentioned NS cases were also included. Data retrieved included study location, year of study and of publication, population characteristics, definition and diagnosis of NS, associated factors, and treatment if applicable. A meta-analysis of associated factors was performed where possible and results were presented as Odds Ratios and visualized as Forrest Plots. Geographic information systems were used for cartographic representations. The quality of the articles included was assessed. Results: Of the 876 articles initially identified, 67 (corresponding to 59 studies) were included in the SR. NS is only present in Central and East Africa. Interestingly, there were reports of NS in Central Africa prior to 2010, earlier than previously thought. The way NS diagnosis was established varies according to studies, and the 2012 WHO classification was used in only 60% of the studies. Approximately 11% of the articles did not meet the quality requirements set for this review. In our meta-analysis, the main factor associated with NS was onchocerciasis (OR = 8.8 [4.8, 15.9]). However, the pathophysiology of the disease remains poorly understood. The lack of common antiepileptic drugs is a significant barrier for the management of head nodding and associated epileptic seizures. Discussion/conclusion: The lack of an operational definition of NS is an obstacle to its diagnosis and thus to its appropriate treatment. Indeed, diagnostic difficulties might have led to false positives and false negatives which could have altered the picture of NS presented in this article. Treatment should take into account nutritional and psychological factors, as well as associated infections. Some risk factors deserve further investigation; therefore, we suggest a multicentric study with an etiological focus using a more operational definition of NS.
... • Onchocerca volvulus has a widespread global distribution while nodding syndrome is only present in a few hotspots. 8,9 • If a necessary cause, every individual must have been exposed to O. ...
... invasion of the CSF or through cross-reactive autoimmunity) in which O. volvulus causes nodding syndrome. 1,9,12 ...
... 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][18][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][18][19]21,22 Wasting and growth retardation occur in 73% and 41% of NS children, respectively. ...
... 10,12,15,[17][18][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][18][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. ...
... 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 consciousness, impairment or loss of speech, inability to stand, urinary incontinence, drooling of saliva and delayed sexual maturity. ...
... Epidemiological studies on NS in Uganda have disclosed correlation between parasitic infection [10], malnutrition [11], environment (insurgency and civilian displacement) [3], and young age. These associations suggest potential multifactorial pathogenesis for NS. ...
... For example, l-tricholomic acid contained in Ustilago maydis [28], known as maize disease, has an affinity for the kainic acid receptor [29]. Noteworthy is the food history of moldy maize was significantly related to NS in Uganda [30]. It is also possible that the emergency relief food may be contaminated with moldy maize-derived substances since eating emergency food supplies were significantly related to NS in Uganda [30]. ...
... Noteworthy is the food history of moldy maize was significantly related to NS in Uganda [30]. It is also possible that the emergency relief food may be contaminated with moldy maize-derived substances since eating emergency food supplies were significantly related to NS in Uganda [30]. Therefore, the ingestion of excitatory amino acids such as kainic acid could be a cause of NS. ...
... In addition, several reports have shown that measles is significantly associated with NS [30,36] and indicated the importance of the BBB because measles causes progressive encephalitis. Furthermore, association between NS with psychological trauma and stress in children from long-lasting war and conflict has been suggested [36,37]. ...
Background
Nodding syndrome (NS) is one type of epilepsy and a progressive disease characterized by nodding symptoms with children in sub-Saharan Africa. The burden for NS children is heavy, not only mentally but financially for themselves and their families, and yet, the cause and cure of NS remain unknown. The kainic acid-induced model in experimental animals is a well-known epilepsy model that is useful for studying human diseases. In this study, we examined similarities of clinical symptoms and histological brain changes between NS patients and kainic acid-treated rats. In addition, we argued for kainic acid agonist as one of the causes of NS.
Methods
Clinical signs in rats were studied after kainic acid administration, and histological lesions including the expression of tau protein and gliosis, were examined at 24 h, 8 days, and 28 days after dosing.
Results
Kainic acid-induced epileptic symptoms were observed in rats, including nodding accompanied by drooling and bilateral neuronal cell death in the hippocampus and piriform cortex regions. In the regions that exhibited neuronal cell death, an increase in tau protein expression and gliosis were found immunohistochemically. The symptoms and brain histology were similar in the NS and kainic acid-induced rat models.
Conclusion
The results suggest that kainic acid agonist may be one of the causative substances for NS.
... Ergot, fumonisin B1 and ochratoxin [7][8][9] have neurotoxic effects. Neurological manifestations can include encephalopathy, movement disorders like choreoathetosis, spasms and ballism, [10] epileptic encephalopathy [11] Algae toxins Cyanobacteria or blue-green algae bloom in higher temperatures in aquatic ecosystem which is associated with climate change. ...
Man and environment have a strong connection with each other for their functioning. Environmental toxins which can be natural or manmade result in the loss of this balance by causing systemic inflammatory response within the human body, with the brain being the most affected target end-organ. These problems are more prominent in Third World countries, where environmental regulations laws are either relaxed or non-existent. These neurotoxins play a very important aetiological role in the manifestation of various neurodegenerative diseases, neurodevelopmental disorders and psychiatric disorders. Environmental neurotoxicity results from inhibition of mitochondrial activity, excess oxidative stress leading to neuroinflammation, and promoting apoptosis and neuronal cell death. Having the know-how of these neurotoxins will provide insight into the process of neurodegeneration and will result in further designing of studies to delve into processes and mechanisms of neuronal regeneration and axonal sprouting. This review highlights the various central nervous system disorders associated with exposure to environmental neurotoxins and discusses the way forward to prevent or halt the process of neurodegeneration.
... Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology [1] named for the characteristic vertical head nodding that appears early in the course of the disease. NS shares some clinical features with other tardive brain disorders such as measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis [2]. Both NS and SSPE have an insidious afebrile onset in children, with behavioral changes and intellectual deterioration, followed by myoclonus, typically beginning with the head, and tonic-clonic and other generalized seizures [3][4][5]. ...
... Given that two independent studies of NS in Kitgum District, northern Uganda, identified a case association with prior measles infection [2], while an earlier study in then-southern Sudan found an inverse association between caregiver reports of prior measles infection and NS in children [3], it is imperative to either confirm or rule out the possibility that NS is a type of post-measles brain disorder. This is particularly relevant considering that children affected by NS were at high risk for infectious disease because of inactive vaccination and drug prophylaxis programs, severe shortages of food and medicine, prolonged civil disturbance, and displacement from their homes [2]. ...
... Given that two independent studies of NS in Kitgum District, northern Uganda, identified a case association with prior measles infection [2], while an earlier study in then-southern Sudan found an inverse association between caregiver reports of prior measles infection and NS in children [3], it is imperative to either confirm or rule out the possibility that NS is a type of post-measles brain disorder. This is particularly relevant considering that children affected by NS were at high risk for infectious disease because of inactive vaccination and drug prophylaxis programs, severe shortages of food and medicine, prolonged civil disturbance, and displacement from their homes [2]. ...
Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition.
