INTRODUCTION
In 1950, Raper and Ladkin 1 reported on a peculiar child development disorder occurring in and around the Mabira rain forest of southeastern Uganda which they described as a syndrome characterized by retarded growth, physical deformities, impaired mental and pubertal development, and epilepsy in some cases. Affected children were apparently born healthy, showing first signs of physical and mental retardation in childhood, earliest during the second or third year of life. 1 The village communities designated the sufferers of this condition as “banakalanga” referring to a local deity named “nakalanga” that they regarded involved in the origination of the ailment. Several clinical and pathological studies could not reveal a medical explanation, 2–5 but it was supposed that the condition should be connected with onchocerciasis. 1,3,4 As early as 1938, from an onchocerciasis area in Mexico, Casis Sacre had described cases who were affected by a disorder resembling Nakalanga syndrome, but no further investigations from this area are available. 6 In the area of the Mabira Forest, after 1965, no more investigation was carried out, and the subject was largely forgotten for a long time.
Only 30 years later, Kipp et al. 7 demonstrated the occurrence of Nakalanga syndrome in the Itwara onchocerciasis focus of western Uganda at a distance of 350 km from the aforementioned Mabira Forest. It was also observed that the prevalence of childhood epilepsy in this area was very high 8 and that a proportion of epilepsy cases had retarded growth and other features of Nakalanga syndrome. 9 The overlap of the symptoms and signs of Nakalanga with those of the more recently described Nodding syndrome 10 led to the consideration that both conditions may be manifestations of one underlying, yet unsolved, pathological process. 11,12 This view is supported by the situation in the Itwara focus where a retrospective analysis of the epilepsy cohort of 1994 confirmed the existence of nodding along with Nakalanga syndrome. 9,13
With the present case report of a patient identified in western Uganda in 1994 and followed until 2018, we illustrate the characteristics of Nakalanga syndrome and point out some of the unclear questions connected with this neglected childhood disorder.
CASE REPORT
On March 14, 1994, a 17-year-old girl was seen during a door-to-door survey on the prevalence of epilepsy in the Kabende parish of Kabarole district, western Uganda. 8 The accompanying mother reported that the epileptic seizures used to start with a jerking movement of the right arm, followed by repetitive downward nodding movements of the head, finally falling to the ground with stiff limbs and loss of consciousness with her eyes open and turned upward or sideways. After 15 minutes, the patient regained consciousness but remained confused for about 20–30 minutes. According to the International League against Epilepsy classification of epileptic seizures of 1981, 14 the seizures were classified as simple partial with secondary generalization. 15 The clinical examination revealed a marked thoracic kyphosis and lumbar lordosis, mental impairment, and retarded growth which had first been recognized when the patient was 10 years old (Table 1).
Case report: Nakalanga syndrome, Western Uganda, 1994–2018
| Date/activity/(reference) | Relevant information (patient history, clinical findings, therapy, and follow-up) |
|---|---|
| 1977–1994/Developmental history from mother’s report on March 14, 1994/(Refs. 8 and 15) | 1977. Born healthy in Kabende parish, western Uganda, onchocerciasis-endemic area. Four healthy siblings. At the age of 2 years, measles with high fever (no loss of consciousness). Purulent otitis at the age of 5 years (side not recalled), since then impaired hearing. Speech, psychomotor development, and growth considered normal up to the age of 10 years. |
| 1987. First perception of delayed growth and starting formation of a deformed thoracic spine. | |
| August 1992. First epileptic seizure (see text for detailed description). | |
| Early 1993. Mental delay noticed, deterioration of speech, and social withdrawal; | |
| August 1993. Last intake of ivermectin (annual CDTI* in the area since 1991). | |
| 1994; March 4 – June 1/First epilepsy survey/(Refs. 8 and 15) | March 14, 1994. Clinical examination: Short stature (height 133.5 cm; z-score −4.62)†, normal nutritional status (body mass index 21.5 kg/m2; z-score +0.18)†; TS‡: B3, P2-3, symmetric thoracic hyperkyphosis/lumbar lordosis, scar at the right thigh, left ear impaired hearing, broad-based gait, prompt and symmetric tendon reflexes, no focal neurological malfunction, understanding and speaking short sentences but unable to cooperate in neurological examination, can help with little things in the house but needs supervision, and poor appetite and eating without assistance. Positive skin biopsy for mf (32 mf/snip)§. Negative serology for Taenia solium. Seizures classified focal with secondary generalization, frequency: 1–2/day. Start PB+ at 60 mg/day (1.7 mg/kg-day). |
| April 10, 1994. Reduced seizure frequency (1–2/week). Improving appetite. Unchanged impaired social competence. Dose PB+ increased to 75 mg/day (2.1 mg/kg-day). | |
| May 10, 1994. Seizures now at 0–1/week, shorter duration. Improved cognition and helps in the garden (e.g., weeding beans and collecting wood). Phenobarbitone increased to 90 mg/day (2.6 mg/kg-day). | |
| May 30, 1994. No seizure over 2 weeks, followed by four seizures during the last week. Unchanged alertness. Dose PB+ increased to 120 mg/day (3.4 mg/kg-day). | |
| Jun 1994–August 1996/6-monthly outreach epilepsy treatment program/(Ref. 16) | December 6, 1994. No seizure since May 1994. Improved strength and mental state (although still impaired). ∼5 minutes after intake of PB+. Phenobarbitone unchanged 120 mg/day. |
| June 5, 1995. No seizure since December 1995. Participates in farm work. Considered mentally normal. No more dizziness at PB+ of 120 mg/day. Received ivermectin at ongoing CDTI*. | |
| February 13, 1996. Seizure free until January 1996. Seizure recurrence since about 2 weeks after PB+ provision run out (1–2 seizure/week; less severe). Restart of PB+ at dose of 120 mg/day. | |
| August 15, 1996. Seizure free, generally fine, PB+ at dose of 120 mg/day (unchanged). | |
| 1998; May 5 – June 9/Program evaluation/(Ref. 17) | May 27, 1998. Seizure recurrence with infrequent seizures (1–2/month) despite ongoing intake of PB+ at dose of 120 mg/day. Irregular drug supplies. Good physical condition, moderate mental impairment. |
| 1998–2018/Epilepsy treatment at local Health Unit/(Ref. 9) | 1998-2001. 6-monthly report about number of patients and mortality to district health services. No records available about details of clinical course and regularity of drug supplies after 2001. Access to PB+ from Kabende health unit (HU opened in 1997). |
| 2018; December 11 – December 15/Second Door-to–Door epilepsy Survey/(Ref. 18) | December 12, 2018. Identification at repeat epilepsy survey after elimination of onchocerciasis in the area. After death of mother, living with the family of her brother. Well integrated in the family and neighbourhood. Not participating in domestic or farm work. Body weight 35 kg, height 128 (z-score −5.39)†; body mass index 21.4 kg/m2 † (normal), waddling but secure gait, and outward strabismus of left eye and good visual orientation. Impaired hearing. High-pitched loud voice. Speaking and understanding short sentences. Moderate mental impairment. Seizures classified as generalized tonic-clonic. |
| 2018; December 18/Follow-up of cohort of first survey of 1994/(Ref. 8) | December 18, 2018. Open in-person interview: After death of mother living with the family of her brother. Well liked in the family and neighbourhood. Complaining of general weakness, correct motor coordination, firm handshake. No partner, no child. Not participating in domestic or farm work. Receives PB+ from Kabende HU. Seizure frequency changing with moon phases (no seizure/three seizures per day). |
| 2018; December 19/Interview with attending health worker | December 19, 2018. Eyewitness account of typical head nodding seizures of the patient, immediately followed by generalized tonic-clonic seizures. Irregular adherence to medication. |
PB+ = phenobarbitone; Time line = sequence of events.
CDTI = community-directed treatment with ivermectin.
Growth Standards of the CDC, 2000; available at: https://www.cdc.gov/growthcharts/cdc_charts.htm.
TS = tanner maturity stages for breast (B1/infantile–B5) and pubic hair (P1–P5) for girls (ref. 11).
mf = microfilaria of Onchocerca volvulus.
Anti-seizure medication was started with phenobarbitone at 60 mg/day, and over 2 months, the dosage was adjusted up to a daily dosage of 120 mg (3.4 mg/kg-day) (Table 1). 16 Thereupon, the patient became widely seizure free from May 1994 until August 1996 and was seen with infrequent seizures during an evaluation of the epilepsy treatment program of the District Health Service in 1998. 16,17 After that, no detailed information is available until 2018 when, in a repeat door-to-door evaluation, she was again identified as suffering from epilepsy with generalized tonic-clonic seizures (Table 1). 18 After completion of the door-to-door survey, 18 the patient was again visited as a part of a follow-up of the patient cohort of the initial survey of 1994 8 that focused on aspects of epilepsy care and psychosocial aspects. At this occasion, the patient promptly recognized the examiners of the earlier encounters and was immediately prepared for an interview. She complained about her general weakness and pain from the scars that had formed after a burn accident before 25 years. She showed to be well oriented in the surroundings of the house and garden of her younger brother where she lived for several years after the death of her mother. With regard to epilepsy, she said that she still had seizures which usually happened in clusters during the full moon. According to her statement, this was not influenced by the intake of the anti-seizure tablets she used to fetch herself from the nearby Kabende health center.
The day after the home visit, an interview was conducted with the attending health worker at the local health center who already had interviewed the patient in 1994 but did not participate in the 2018 repeat door-to-door evaluation (C. M.). Being employed as an enrolled nurse at Kabende health center since 2008, she was considered a key person to discuss the question whether in the area of Kabende any cases with nodding syndrome still could be found because these had been identified in the area in 1994. 13 For illustration of what was known about head nodding from northern Uganda and southern Sudan, in this meeting, three video sequences of head nodding seizures were shown. 19–21 When faced with these videos, C. M. spontaneously stated that definitely in the past this type of seizures was very common but presently she knew of only two persons, one of them the women of this case report. She confirmed that she had eyewitnessed a typical head nodding seizure followed by a generalized seizure when the woman presented at the health center 3 weeks ago. She also reported that the woman frequently came late for getting her medication and assumed that seizure recurrence was triggered by treatment interruptions.
DISCUSSION
The documented findings of the presented case fit well with the proposed criteria for a case definition of Nakalanga syndrome (Table 2). 11 A critical comparison of this definition with that for nodding syndrome consented at a WHO conference in Kampala, Uganda, in 2012 22,23 shows the similarity between the two disorders and that the key feature distinguishing Nakalanga from nodding syndrome is indeed the hallmark symptom of head nodding seizures. The eyewitness account of head nodding by the attending nurse of the local health center, a health worker with many years’ experience of treating persons with epilepsy, is evidence that the woman described in this report meets the criteria of both Nakalanga syndrome and confirmed nodding syndrome.
Criteria for case definitions of Nakalanga and Nodding syndrome applied to the presented case (adapted from Föger et al. 11 and Dowell et al. 23 )
| Proposed criteria for Nakalanga syndrome | Consented criteria for nodding syndrome | ||
|---|---|---|---|
| Suspected case | Suspected case | ||
| Not specified | + | Reported head nodding in a previously healthy person | |
| Probable case | Probable case | ||
| Major criteria (all mandatory) | Major criteria (all mandatory) | ||
| Born healthy | + | + | Reported head nodding in a previously healthy person (= suspected case) |
| Onset in childhood | + | + | Age 3–18 years at onset (of head nodding) |
| + | Nodding frequency 5–20 times/minute | ||
| No alternative explanatory condition | + | ||
| Plus one or several symptoms of developmental disturbance (a – d): | Minor criteria (one criterion needed) | ||
| a) Stunting, growth failure | + | + | Delayed physical development |
| b) Wasting, emaciation | − | ||
| c) Retardation of sexual development | − | − | Delayed sexual development |
| d) Mental impairment | + | + | Cognitive impairment |
| Minor criteria (optional) | |||
| Epileptic seizures | + | + | Other seizures |
| Kyphoscoliosis | + | ||
| Similar cases in the surroundings | + | + | Clustering of cases in time and space |
| Facial dysmorphia | n.r. | ||
| Confirmed case | Confirmed case | ||
| Not specified | + | Observed and recorded by a trained health care worker | |
| n.r. | Videotaped head nodding episode | ||
| n.r. | Video/electroencephalography/electromyography documenting head nodding as atonic seizures | ||
+ = criterion recorded as present; − = criterion not present; n.r. = criterion not recorded.
Little is known about the long-term course of Nakalanga syndrome. The studies of the 1950s and 1960s in Mabira assumed that the disorder is associated with substantial morbidity and mortality, but no longitudinal data were collected. 1–5 A follow-up of over 7 years of a small cohort of Nakalanga cases in western Uganda, including the presented case, found a 20-fold increase in the risk of dying compared with the standard population. 9 The fact that only one (present report) of the eight Nakalanga cases living in the high-endemic villages of Kabende parish in 1994 was found during the repeat cross-sectional survey in 2018 18 is additional evidence of high mortality. We can only speculate about possible explanations why, in contrast to the others, this patient survived for a long period. Possible protective factors might have been that 1) antiepileptic treatment was started early, 2) the patient received ivermectin since 1991, and 3) the patient received supportive care from her family. The benefit of early anti-seizure treatment for patients with nodding syndrome was also shown by the study of Idro et al. 24 from northern Uganda.
The close connection between the clinical features of Nakalanga and nodding syndromes is an indication that both conditions should be induced by one common underlying pathological process. As already mentioned, the authors of the early studies on Nakalanga in the Mabira Forest of southeastern Uganda saw a geographical connection with Onchocerca volvulus infection. 1,3,4 This link was also obvious in our study area in the Itwara focus of western Uganda where Nakalanga patients were frequently found in highly onchocerciasis endemic villages, but were rare in hypo-endemic villages. Case–control data of 31 persons with Nakalanga syndrome and 28 healthy controls from the area demonstrated that O. volvulus infection was significantly more frequent in persons with Nakalanga syndrome. 7 After onchocerciasis was eliminated from the Mabira focus by vector control in the early 1960s, 25 Nakalanga syndrome disappeared from this area. 7 Accordingly, in the Itwara focus, no new cases of Nakalanga syndrome were found 17 years after successful interruption of onchocerciasis transmission. 18 With regard to nodding syndrome, increasing evidence supporting a causal relation with onchocerciasis was gathered from several areas: 1) A positive correlation between onchocerciasis endemicity level and prevalence of nodding syndrome was demonstrated in the Itwara area 13 and in the Mahenge focus of southern Tanzania 26,27 ; 2) Case–control studies consistently found a positive association between O. volvulus infection status and nodding syndrome 28–30 ; 3) As for Nakalanga syndrome, in the Itwara focus, no new cases of nodding syndrome were found after elimination of onchocerciasis by community-directed treatment with ivermectin and vector control 18 ; 4) A recent study from southern Sudan demonstrated that patients with nodding syndrome had higher microfilarial counts in skin biopsy, more frequent seizures, and more severe cognitive disability than persons with other forms of epilepsy. 31
Additional evidence that O. volvulus can damage the brain originated from numerous epidemiological studies on the relationship between onchocerciasis and epilepsy at large. These demonstrated that throughout the endemic areas of sub-Sahara Africa, epilepsy prevalence increases at an exponential rate with that of onchocerciasis, 32 that there is a robust positive association between O. volvulus infection status and epilepsy, 33,34 and that the risk of a young individual exposed to onchocerciasis of developing epilepsy is increasing with infection intensity. 35,36 This link between onchocerciasis and epilepsy was termed “river epilepsy” 32 or “onchocerciasis-associated epilepsy.” 33 Both nodding and Nakalanga syndromes are regularly observed in areas with a concomitant high prevalence of other forms of epilepsy: in particular, epilepsy with generalized convulsive seizures. 8,10,13,37–43
The present case report shows that patients with Nakalanga and nodding syndromes, despite the severity of the disease, can survive over a long time. Our observation also adds to the encouraging experience of others 24 that anti-seizure treatment and supportive care may be effective to prolong and improve the life of the affected children. Areas where onchocerciasis is still hyper-endemic should be systematically examined for the occurrence of Nakalanga/nodding syndrome and for excessive epilepsy prevalence. Appropriate epilepsy care needs to be established in these areas. 17,44 The current case definitions for Nakalanga and nodding syndromes 10,11,22,23 do not reflect the growing knowledge about their interconnections with other forms of epilepsy, and with onchocerciasis. This should be considered in future revisions.
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