Nodding syndrome: origins and natural history of a longstanding epileptic disorder in sub-Saharan Africa

Background : Repetitive involuntary head nodding was first reported in the 1960s in the Wapogoro tribe of Tanzania. Objectives : We describe the natural history of head nodding in the Wapogoro tribe, with special reference to the earliest reported dates of onset. Methods : We analyzed clinical data from 150 historical patients seen between 1960 and 1971. Results : Head nodding with or without grand mal convulsions was present in 33/150 (~20%) cases, was mostly familial and equally distributed by gender. Age at onset of head nodding ranged from 2-22 years (mean: ~10 years) in the period 1934-1962. Head nodding preceded onset of grand mal convulsions by up to 12 months, and motor and psychomotor deficits indicative of brain damage developed with time. Fourteen of the 33 cases died at 13-39 years of age (mean: ~20 years) while nineteen aged 16-28 years (mean: ~16 years) were still alive. Conclusion: Historical accounts of head nodding ( amesinzia kichwa , Swahili ) among the Wapogoro tribe fit the August 2012 World Health Organization (WHO) case definition of probable Nodding Syndrome. Reported to have existed in this population for at least 80 years, Nodding Syndrome is a progressive seizure disorder that leads to generalized convulsions ( kifafa ), brain damage and d eath.


Introduction
Nodding Syndrome is a generalized seizure disorder that appeared de novo in 1991 in Western Equatoria, South Sudan, and some years later in northern Uganda. 1,2The affected populations 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 repeated displacement from their homes.A case-control study carried out in 2002 in then-southern Sudan found a positive case association with two parasitic nematodes (Onchocerca volvulus, Mansonella perstans) and an inverse association with childhood measles infection.Among non-infectious environmental exposures, food contamination with fungal neurotoxins could not be excluded 2,3 .Others have suggested without evidence an etiologic role for heavy metals, pesticides, or warfare chemicals.Clues as to the origin, cause and natural history of Nodding Syndrome may be gained from studies of a Tanzanian focus of epilepsy 4 , where, in the 1960s, one of us (L.J-A.) observed repetitive head nodding (amesinzia kichwa, Swahili) among members of the rural Wapogoro community of the Mahenge highlands of Tanganyika (now the United Republic of Tanzania), 5 where malnutrition, infectious disease (notably onchocerciasis) and grand mal convulsions (kifafa, Swahili) are highly prevalent [5][6][7] .While the clinical features, treatment and course of epilepsy among patients seen at the Mahenge Epilepsy Clinic have been extensively documented elsewhere, including a 30-year follow-up in 1992 of the available caseload 8 , there has been no systematic examination of clinical notes from the early years (1959  onwards).The objective of this study is to illuminate the traceable origins, clinical course and outcome of amesinzia kichwa among the Wapagoro.Based on the analysis of data extracted from clinical notes of 150 patients seen by L. J-A between 1960 and 1971, we conclude that amesinzia kichwa, and, hence Nodding Syndrome, has been present in this community for at least 80 years.This conclusion should be helpful in distinguishing between etiologic hypotheses for the recent epidemics of Nodding Syndrome in northern Uganda and South Sudan.

Methods
In the 1960s, as today, the Wapogoro tribe lived in the Mahenge mountains, a remote area of central Tanganyika.While the history of these people is unclear, they appear to have lived with other tribes on the lowland Ulanga plain until 1750, when the chief began to move his clansmen to the mountains.Some time later (circa 1850), the Wapagoros were reported to have fled to the Mahenge mountains to avoid conflict with the Ngoni, an aggressive tribe that had moved into the Ulanga plain.The Wapagoro settled in small villages spread out in isolated regions in the mountains. 9,10n 1959, L. J-A established an outpatient clinic for the Wapogoro tribe at the Kwiro Mission in Mahenge.Staffed by a single registered nurse, the mission station provided medical care for people who came for treatment from mountain villages and for the homeless and handicapped.Conditions in the clinic were primitive (no electricity and running water), and medical equipment was confined to a stethoscope, reflex hammer, thermometer and simple microscope.Several adult patients presented with severe burn wounds acquired by falling into a fire during a convulsive attack (kifafa).Since the community feared kifafa and considered the disorder to arise from an evil spirit that could be passed from one person to another, kifafa victims were shunned and rescued from fire by only the closest of relatives.While traditional medical healers provided treatment for burns, the community considered kifafa untreatable until L.J-A began to dispense phenobarbital, which successfully reduced or eliminated grand mal seizures. 8e analyzed the unnamed standardized case records of ~180 patients with kifafa seen by L.J-A at the Mahenge clinic between 1960 and 1971, with follow-up for up to 10 years.At initial presentation, each patient was given a simple physical, neurological and psychological examination, the nutritional state assessed by observation, a blood sample taken to determine hemoglobin status, and treatment (including iron, phenobarbital) initiated as required.Patients were followed periodically by the nurse (monthly where possible) and antiepileptic therapy adjusted as directed by L.J-A.Histories given by the patient in Swahili were simultaneously translated to and recorded in English and later summarized by L.J-A on a standard record sheet.
Thirty of the 180 cases were omitted for lack or paucity of recorded data.Data for 150 cases included: (a) family and patient history, the latter including sex, age, and year of onset; age at first observation, follow-up duration, and age at death; history of birth trauma, antecedent illnesses or febrile convulsions; frequency, type, laterality, and description of attacks, including aura, head nodding, and state of consciousness; (b) physical examination for nutritional state, liver and spleen size, and skin burns, (c) neurological examination of cranial and peripheral nerves; for pyramidal, extrapyramidal, or cerebellar signs; and for higher cortical function (intelligence, psychological function), and (d) laboratory examination of blood for % hemoglobin (Hgb), where 80% Hgb was taken as within normal limits (wnl), <60% Hgb as evidence of anemia, and <40% Hgb as indicating the need for iron supplementation.

Results
Head nodding with or without (n=4) grand mal seizures was reported in 33/150 cases (16 females and 17 males) (table 1), while the balance at the time of their clinic visit had mostly primary generalized seizures (convulsion group) without head nodding.The latter were born between 1911 and 1960, and the head-nodding group between 1924 and 1955.The earliest report (1934) of head nodding involved a 10-year-old female who died at age 39.While almost all head-nodding cases (~95%) were children of epilepsy-free parents, most had familial associations with kifafa and/or amesinzia kichwa either via affected siblings or through either parent.One case in the convulsion group had a sibling with head nodding, as well as paternal relatives who suffered from convulsions.The age of onset of seizures for the convulsion group ranged from 2 months to 36 years, while those cases with head nodding ranged from 2-22 years (mean: ~10 years).Nineteen of the 33 nodding cases were aged 16-28 years (mean: ~16 years) and 14 had died at 13-39 years of age (mean: ~20 years) as indicated in table 1.
Most patients died at home and no autopsies were performed, of 26 cases in which a cause of death was noted, 9 had an unknown cause, 7 died in status epilepticus, and individual cases died in states associated with "bad headaches and frequent seizures", "neglect and epilepsy", "most probably from epilepsy", "complete mental derangement", marasmus with and without leprosy, "high fever" (probably malaria), "pneumonia", "after 2 days of unconsciousness" and "or fell into fire".Unlike the kifafa group, where drowning of adults was not infrequently reported, 8 children with amesinzia kichwa were guarded and restricted to their homes.
In the head-nodding group, drowsiness, narcolepsy or head nodding frequently preceded onset of grand mal convulsions (when present) by up to 12 months.When recorded, onset of head nodding occurred while eating and/or at night, with nodding occurring before, between, or following grand mal seizures.Some patients reported experiencing an aura (n=12).Physical examination of headnodding cases typically revealed a thin, neglected child, often small and underdeveloped for age, and in either a poor (n=18), good (n=14) or unrecorded (n=1) nutritional state (table 2).Burn scars and tongue scars were present in some.Anemia was evident in all but 3 cases, and liver and spleen examination was usually unremarkable.Neurological signs included extremity hyperreflexia (n=9) and areflexia (n=4) usually involving all extremities, but pathological reflexes (e.g.extensor plantar) pathognomonic of pyramidal-tract dysfunction were absent.Possible signs suggestive of extrapyramidal involvement were evident in one-third, including mask-like facies (n=9), monotonous grating voice (n=4), and/or hypersalivation (n=4).Intelligence was judged as bright (n=2), normal (n=14), low to dull (n=13), or moronic (n=4).Psychological examination revealed normal (n=9) and abnormal states, including timid/restless/frightened/anxious (n=9), depressed/uninterested/absent-minded (n=8), psychomotor retardation (n=3), or near-mute/mute (n=3).

Discussion
Head nodding among the Wapogoro fits the WHO case definition of probable Nodding Syndrome developed in August 2012 by international scientific consensus 11 .Agreement was unanimous that clinical signs of this epileptic disorder were indistinguishable among affected populations of south Sudan, Uganda and Tanzania.Nodding of the head, staring and automatisms (chewing, verbal) have also been described in seizure-prone tribal groups in Liberia. 12,13e document the earliest known cases of head nodding (amesinzia kichwa) in an epilepsy-prone population of Tanzania, 5 with cases of head nodding reportedly dating from 1934.This period appears to pre-date the introduction to this population of manmade chemicals with neurotoxic potential, such as pesticides.Because Nodding Syndrome in the Wapogoro affected mostly undernourished, smallfor-age children in a marginalized population at high risk for epilepsy, onchocerciasis 14 and seasonal food shortages, the search for etiology is logically focused on infectious disease and/or nutritional factors, the latter including naturally occurring chemical components in food.The association in some cases between head nodding and food/eating as a precipitating factor 6 has been noted in another epilepsy-prone population with high prevalence of onchocerciasis, 2 and the possible role of certain plant and fungal neurotoxins in Nodding Syndrome has been discussed. 3Genetic factors in kifafa have been considered previously 15 but parents of children with Nodding Syndrome were usually free of epilepsy, and familial association of disease can also arise from common exposures to etiologic agents.Febrile convulsions were an antecedent event for amesinzia kichwa in up to 20%. 6atient histories of cases from Uganda and South Sudan suggest that Nodding Syndrome may begin with a prodromal period marked by drowsiness, absences, and staring, evolve into different schedules of repetitive head nodding and, with time, advance in most cases to grand mal seizures .The Wapogoro fear amesinzia kichwa in a child because it portends extant or impending convulsive kifafa.Affected subjects are often of small stature, poorly nourished, shy and neglected.Left untreated, children and young adults developed neurological signs indicative of psychomotor and motor-system involvement, including parkinsonism in some cases, signs of which have not been described in other foci of Nodding Syndrome.Recent studies 6,7 utilizing magnetic resonance imaging have revealed subcortical frontal gliosis and/or hippocampal sclerosis/atrophy in a few Wapogoro cases of Nodding Syndrome with or without other types of seizures.In sum, the natural history of Nodding Syndrome is one of a progressive seizure disorder attended by evolving brain damage likely caused or amplified by repeated hypoxia/anoxia during the convulsive event.

Table 1 :
Head nodding cases: gender, lifespan, onset year and age, familiality, nutritional status, exam age, follow-up and notable history

Table 2 :
Head Nodding cases: physical, neurological and psychological findings

Table 2 :
Head Nodding cases: physical, neurological and psychological findings