Clusters of children living half a world away have the most seasoned global disease experts stumped.
The children have an epileptic encephalopathy called nodding syndrome, a neurological condition for which there is no known cause and that affects thousands in rural African villages, according to Dr. Scott F. Dowell, director of the division of global disease detection and emergency response at the Center for Global Health (CGH), Centers for Disease Control and Prevention.
Dowell and Dr. James Sejvar, a CGH medical officer, shared what is known to date about the mysterious condition at a recent grand rounds session sponsored by the National Institute of Neurological Disorders and Stroke. Dowell reviewed findings from 4 case-control studies involving 486 subjects including 121 age- and village-matched case-control pairs in South Sudan and 122 pairs in Uganda. Some 10 investigations have been conducted; only the 4 have been case controlled.
Dr. Scott F. Dowell (l) and Dr. James Sejvar, both of the Centers for Disease Control and Prevention, field questions about nodding syndrome at their grand rounds presentations on the mysterious illness that affects children in rural African villages.
Dr. Avindra Nath, NINDS clinical director, said the forthcoming vitamin B6 trial will provide an opportunity to follow patients prospectively and to collect biological samples from well-characterized patients.
Photos: Bill Branson
Initially described in Tanzania during the 1960s, the syndrome causes children to experience epileptic episodes that involve nodding their heads forward 10 to 15 times a minute in a non-rhythmic fashion for about 5 minutes during which they do not respond to commands, Sejvar explained. EEG findings from his case-control study in Uganda confirmed the presence of atonic seizures.
The nodding episodes are most often triggered by the aroma of food or exposure to cold weather, suggesting that the cause of the episodes may have a reflexive component, Dowell added.
Within a few years, most children with the syndrome progressively worsen. The nodding episodes, which at first occur a few times a week, start happening several times a day and are increasingly followed by general confusion, incontinence and lethargy. Eventually, multiple seizure types develop involving convulsions and staring spells. Mental capacity greatly diminishes and school performance declines. Some families resort to securing the children to trees to keep them from wandering and harming themselves by drowning, falling or fire exposure. Early mortality is common, though it is not clear at this point if the deaths are due to the syndrome’s progression or the circumstances that it creates.
Children with the syndrome generally are reported to be healthy until nodding episodes begin. Fully 93 percent of the children evaluated in Uganda were ages 5 to 15 years, Dowell said.
Geographically, the cases are concentrated in rural pockets of South Sudan, Uganda and Tanzania, affecting as many as 40 per thousand children in some villages. Yet these clusters are separated by hundreds of kilometers with no known cases. Urban populations appear unaffected.
Among the speculated causes of nodding syndrome is Onchocerca volvulus, an infection spread by blackflies that breed in fast-flowing streams and then inject their larvae into a human host. That same parasite causes onchocerciasis, otherwise known as river blindness, which is endemic in regions where nodding syndrome also is prevalent. In one of the case-control studies in South Sudan, Onchocerca infection was more common among the 38 cases compared to controls (76 percent vs. 47 percent).
Genetics also may be a contributing factor; polygamy is practiced in the regions. A genetic mutation that, for example, makes some children less responsive to ivermectin, the treatment commonly used for onchocerciasis, could quickly gain a foothold in populations where polygamy or inbreeding is practiced.
Many of the affected communities were displaced by civil war conflicts in the late 1990s and toxin exposure during that period cannot be ruled out. Consumption of improperly prepared cassava root, a common staple in the region, can lead to cyanide poisioning.
Another hypothesis involves nutritional deficiencies. In at least two of the case-control studies, children with nodding syndrome were more likely than controls to have vitamin B6 (pyridoxine) deficiencies. This is intriguing, Dowell said, because pyridoxine-dependent seizures are known to resolve with vitamin B6 supplementation. However, most of these types of seizures begin before age 3 years, so the relevance of vitamin B6 deficiency in terms of nodding syndrome is still unclear.
As part of a general intervention, many of the children have been taking a multivitamin, but therapeutic levels may be several 100-fold higher. A clinical trial to investigate the effects of therapeutic levels of vitamin B6 among children with the syndrome is set to launch in 2013.
Dr. Avindra Nath, NINDS clinical director, said the vitamin B6 trial is an excellent idea. While it may not lead to a silver-bullet treatment, “it will certainly be an opportunity to follow patients prospectively and collect biological samples from well-characterized patients, all of which will be very useful in studying the disease.”