Treatment of Nodding Syndrome - A Randomized Blinded Placebo-Controlled Crossover Trial of Oral Pyridoxine and Conventional Anti-Epileptic Therapy, in Northern Uganda - 2012

Nodding Syndrome (NS) is described as an epileptic seizure disorder and has been documented in various geographic areas of sub-Saharan Africa. Jilek et al, 1962, first described several children with attacks of 'nodding head' in Mahenge, a region in southern Tanzania (1,2,3). A missionary doctor described children in southern Sudan in the mid-1990s, where it was first noted in the Lui and Amadi villages of East Mundri county and the Lui region of western Equatoria; a medical NGO then reported the condition to WHO in 1997. An estimated 300 cases were reported in 2003 from this region (4, 5). Winkler et al., using data from Tanzania provided a clinical classification of seizures, semiology and socio-cultural aspects suggesting it was a syndrome (referred to as "head-nodding syndrome") and a form of epilepsy (6, 7). In 2008 and 2009, reports of an illness consistent with NS were reported in Kitgum and Pader districts, northern Uganda. Kaiser et al, in 2009, referred to the phenomenon of head nodding as possibly constituting a feature of an epileptic syndrome caused by O. volvulus (8).

Descriptions of the features of NS appear similar between reports (Appendix A). Nodding is frequently described as occurring in response to some stimulus, frequently being the presence of food or exposure to cold (4, 5, 6, 7). The nodding consists of repetitive bobbing or nodding of the head, sometimes associated with loss of muscle tone in the trunk and upper extremities (6, 7). Consciousness may or may not be impaired during the nodding episodes. The syndrome has been described to be progressive, with gradual neurological deterioration and development of additional seizure types, developmental regression, cognitive decline, and sometimes reportedly resulting in serious injuries or death both due to accidental falls into fires or wells during seizure episodes. Treatment with conventional antiepileptic medications has anecdotally been reported to result in some symptomatic improvement of both nodding and other seizure types. Health workers in southern Sudan report that children who start treatment early and on regular basis have seizures less frequently (9).

The cause of NS is unknown. Various factors and exposures have been postulated to cause NS, including exposure to munitions, prior history of measles infection, consumption of baboon meat and sorghum, and others. Two recent case-control investigations, one conducted among children with NS in Uganda during 2009 - 2010 and another conducted in S. Sudan in 2011 (below) have not supported these associations. One risk factor that appears to consistently demonstrate an association with NS is evidence of infection, past or present, with the microfilarial parasite Onchocerca volvulus, or a similar microfilarial parasite that is serologically cross-reactive with Onchocerca. O. volvulus is transmitted by black flies. Clinical manifestation of onchocerciasis is mainly ocular, with resultant vision loss due to inflammatory keratitis ("River Blindness"). A significant association of NS with detection of O. volvulus microfilariae in skin snips was observed in a case-control investigation in Sudan in 2001 - 2002, and in an assessment in Tanzania (84% of 62 children with NS had microfilariae or O. volvulus nucleic acid in skin snips). Various studies and reviews have identified an association between onchocerciasis and epilepsy in general (5, 10, 11, 12, 13, 14, 15, 16, 17, 44, 46). A high prevalence of seizure disorders in onchocerciasis endemic areas was noted in Western Equatoria in 1946.

In the WHO investigations conducted in southern Sudan in late 2001, skin snip positivity and higher microfilaria loads of O. volvulus were found in children with NS when compared to children without the condition, consistent with similar observations of a possible association between seizures and onchocerciasis from other studies (5, 10, 11, 12, 13, 14, 15, 16, 17, 44, 46). These, and subsequent investigations in 2002 by WHO could not identify any environmental pollutants, chemical agents or food toxins, nor several infectious agents, as possible causes for the seizures. EEG among 31 children assessed showed progressive epileptic encephalopathy.

In December 2009, a team from the US Centers for Disease Control and Prevention (CDC) assisted the Uganda Ministry of Health and the WHO in the investigation of the occurrence of NS in Kitgum / Pader regions of northern Uganda. A total of 51 cases with reported NS, and 93 household or friend controls were identified for the case control investigation and additionally, 23 subjects with reported NS were enrolled in a case series that underwent thorough medical and neurological assessments.