The emergence of “nodding disease”

The emergence of “new” diseases is a complicated issue. “New” diseases often just means “new to biomedical science.” Viruses like Ebola and HIV were certainly circulating in Africa in animal reservoirs for decades, and probably millenia, before they came to the attention of physicians via human infections. Hantavirus in the American southwest has likely infected many people, causing pneumonia of unknown origin, before the Four Corners outbreak led to the eventual identification of the Sin Nombre virus. Encroachment of humans into new areas can bring them into contact with novel infectious agents acquired via their food or water, or by exposure to new disease vectors such as mosquitoes or ticks. Occasionally, emerging diseases may be truly “new”–such as recombinant influenza viruses that resulted from a mixture of viruses from different host species to form a unique variant, different from either parent virus.

Nodding disease is one of those that has only recently appeared on the radar of those of us in public health, although it is not truly a “new” disease. It was first described 40 years ago, but this syndrome has been sufficiently rare as to not merit significant medical attention until 2010. Outbreaks of nodding disease have now occurred in South Sudan, Tanzania, and Uganda, affecting thousands of children. The disease first presents as cognitive difficulties; then the nodding starts, especially when children are provided food. They experience further cognitive decline, and ultimately regress to an almost infantile stage, where parents cannot leave them unattended for fear they may wander off or injure themselves by accident. Death appears to often be a result of such accidents: (drowning, falling into a cookfire) or starvation, as the seizures in the late stages of the disease seem to make it virtually impossible for the child to eat. No one is known to have recovered from the disease.

While the cause(s) still remain mysterious, studies have been done trying to determine risk factors for disease development. A recent CDC-assisted study, for example, was carried out in the new country of South Sudan. This examined 38 matched cases and controls and examined dietary as well as infectious disease factors, looking at issues such as vitamin deficiencies, a history of hunger, and current infection with the parasite Onchocerca volvulus.

This particular agent is interesting, as the nematode already causes a well-known disease, river blindness. Like many parasites, the life cycle of O. volvulus is fascinating and complicated. Humans are the main host, who are initially infected via the bite of the black fly, which was herself infected with O. volvulus from a previous human meal. After inoculation, the nematode larvae migrate to the subcutaneous tissue of their human host, where they multiply and mature over the course of 6-12 months, eventually mating and producing microfilariae–little baby worms, up to 3000 per day per female nematode. It’s this life stage that are then ingested by black flies during a daytime meal, when the microfilariae migrate to the host’s skin. Within the fly, they will mature through three larval stages, ready to infect another human host.

How then do these worms cause blindness, if they live mainly in the subcutaneous tissues and, sporadically, the skin? The microfilariae also migrate to the surface of the cornea, and when these organisms die, they cause an intense immune response. Interestingly, this response seems to be due not to the worms themselves, but to their Wolbachia symbionts–bacteria species notorious for infecting parasites (and insects) and causing all sorts of weird things to happen. Repeated episodes of this inflammation can lead to keratitis, and the cornea eventually becomes opaque. O. volvulus can also cause intense skin itching, leaving dead and discolored patches of skin in addition to the characteristic blindness. In all, it’s a nasty disease but one that is relatively simple to treat if caught early, either with antiparasitic drugs or even with antibiotics such as tetracycline to kill the Wolbachia. The disease can also be prevented by fly mitigation and preventative doses of anti-parasitic medicines.

Testing for O. volvulus is relatively simple. The MMWR study used a “skin snip”–just as it sounds, taking a small piece of skin from the patient and examining it for microfilariae. However, this has the limitation that it may miss early infections (where microfilariae have not yet developed and spread) or mild infections (where there are fewer organisms per square millimeter of skin sample). They note that they also took blood samples to examine antibody responses, but those data were not yet available.

What they found was interesting. In one village, Maridi, they found a matched odds ratio of 9.3 (with the cases being more likely to be currently infected with O. volvulus than the controls), which agrees with an earlier study done in Tanzania which found high levels of infections in cases. However, no healthy controls were tested for comparison in that publication. Furthermore, in the South Sudan study, no statistically significant difference in parasite infection was found between cases and controls in the second village, Witto. Why the dramatic difference between the two locations in the same country? Don’t know. It could simply be related to small sizes (only 25 pairs were examined in Maridi, a “semi-urban” area, and 13 in Witto, described as rural). We also don’t know anything about temporality–were the patients affected before they developed nodding disease, or subsequent to the start of symptoms? Even though many questions remain, the Ugandan government is taking steps that look as if they believe a cause of nodding disease has been found, and that O. volvulus is that cause. While additional measures to stop the spread of the parasite are probably a good idea in any case (reducing river blindness is also good), I certainly wouldn’t call this case closed, and neither did the individuals speaking on this issue recently at ICEID, where this outbreak was discussed in at least two sessions I attended.

There is biologic plausibility for O. volvulus to cause a seizure disorder. Several other types of parasites can cause epileptic conditions, including the tapeworm Taenia solium, which can originate in beef or pork products. Could it be that O. volvulus is getting into the brain and causing pathology, leading to seizures? The 2008 Tanzanian study suggests no, as the cerebral spinal fluid was tested in 42 patients and found to be negative for O. volvulus DNA in all patients.

With some emerging diseases, there is the risk that the incidence of a disease is increasing due only to awareness of an illness–the more doctors that recognize it, the more cases they will diagnose. However, there is anecdotal evidence that this isn’t the case with nodding disease:

Dr. Abubakar said in an interview that while the syndrome is known to have existed for some time in South Sudan, the recent spike in reported cases could only partially be explained by wider awareness and better surveillance. “It’s not only local authorities but local NGOs saying more children have been affected,” he said. Particularly striking, he said, is that in South Sudan “there are a number of displaced people from another location who did not have nodding. But after the displacement, when they moved to affected areas, after 2 years the children started developing the syndrome.”

Additional studies and more thorough surveillance are needed to confirm that this is true, which would suggest a localized focus of disease in multiple different areas (which does seem to be the case at this point in time).

The migration aspect is intriguing, suggesting some sort of environmental exposure–if it was simple genetics, where the children were living shouldn’t matter. However, this puts us back almost as square one, examining what is present in the local environment–both infectious and non-infectious agents including heavy metals and various toxins.

The work investigating nodding disease is still in its infancy, but already “nodding disease” has affected more individuals than all of the recorded cases of Ebola. Now that there is recognition of the disease, and some international support for research into its causes, hopefully better treatment and prevention efforts will follow.

Works cited

WInkler et al, 2008. The head nodding syndrome–clinical classification and possible causes. Epilepsia. 49(12):2008-15. Link.

CDC. 2012. Nodding Syndrome — South Sudan, 2011. MMWR. 61(03);52-54. Link.