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.

Comments

  1. #1 Orac
    March 27, 2012

    You obviously have it all wrong. The antivaccine cranks at Age of Autism know what’s causing nodding disease. It’s obviously pharmaceutical trials and vaccines! How can you be so blind?

    http://www.ageofautism.com/2012/03/ugandas-children-are-dying-are-pharmaceutical-trials-to-blame.html

    Truly, the confusing of correlation with causation is strong in Mary Romaniec (the author of the AoA nonsense).

  2. #2 Tara C. Smith
    March 27, 2012

    How shocking that they’d exploit this. Not to mention that it really doesn’t have much in common with narcolepsy at all…

  3. #3 Mark Struthers
    March 27, 2012

    The cause of nodding disease is a mystery, but Tara is ‘shocked’ by the idea that vaccines could possibly be involved. Scientists – like Tara – don’t know the cause or causes of autism, but are sure that the increasing prevalence of autism has nothing whatever to do with vaccines. Give me strength!

  4. #4 NJ
    March 27, 2012

    Oh, great. An AoA nimrod has escaped and landed here instead of Orac’s.

    Despite your fervent religious beliefs, Mark, empirical data has shown no link between vaccines and autism.

    None.

    Oh, about to mention Wakefield? Too bad he’s been shown unambiguously as a fraud. Your best bet is to go stand quietly in a corner until your IQ rises to some minimal level.

    Like zero.

  5. #5 Mark Struthers
    March 27, 2012

    I spy with my little eye … a rat’s posterior … and it’s big pink knickers are on fire … the stupid, it burns.

  6. #6 eli
    March 27, 2012

    Excellent post; tons of great information. I wonder if the Maridi vs Witto differences could be explained by a co-infecting pathogen? Perhaps the unknown pathogen shares the same route of infection as O. volvulus, but was less prevalent in Witto. Is the baseline prevalence of O. volvulus similar in Maridi and Witto?

  7. #7 Tara C. Smith
    March 27, 2012

    Good questions and I have no additional info to offer, unfortunately. It sounded like the investigators still have a lot of information to analyze and are looking to do longitudinal investigations in both areas, so hopefully some of that will come to light from this research. I didn’t hear them mention anything specific about baseline prevalence, but it sounded like it was fairly high in both areas.

  8. #8 wombat123
    March 28, 2012

    Dr Struthers – which childhood vaccines do you routinely recommend for your patients?

  9. #9 Mark Struthers
    March 28, 2012

    That’s a very clever question, wombat123. Go to the top of the class!

  10. #10 David Green
    March 29, 2012

    Would post-mortem macro and microscopic examination of the parts of the brain known to be associated with satiety be any help in tracking down possible causes?

  11. #11 Anne Mitchell
    April 3, 2012

    Hi Tara, you mentioned Wolbachia infecting the nematode. Has anyone looked at the incidence of Wolbachia in O. volvulus versus disease incidence in different regions? And what about the increase of symptoms after eating? Raised blood sugar is stirring something up, is it the nematode or Wolbachia or something else. Very puzzling, I hope we can sort it out soon. Regards Anne

  12. #12 Judy Pommer
    April 3, 2012

    Has anyone looked at the BPA in the plastic containers that they are using to carry their water as well as store and prepare their food in.Perhaps the childrens systems have been weakened by the parasitic worm and are therefore susceptible to the toxins in BPA.We have had it removed from our food and water sources as we are aware of the dangers it causes,it should also be removed from use in poorer countries.

  13. #13 Brian Wearing
    April 3, 2012

    This looks shockingly similar to an epilepsy syndrome that my daughter has suffered from for 6+ years(in the beginning she had the nickname ‘noddy’ from some of the children at school). She began falling when the first drug was started. After trying a total of seven drugs the doctors finally gave in and let us try the Ketogenic diet we had asked for after the 2nd drug. They had told us it wouldn’t work for this type of epilepsy. By then she had no intellect left, was incontinent, mute and had to be in a wheelchair or held up by two helpers. She was still on three drugs at the start of the Ketogenic diet over a year ago. We are now weaning her off the last one. She became continent again after eliminating #1 Lamotrigine, stopping #2 Clobozam had no effect and she has now started talking again as we have begun reducing the dose of #3 Keppra. Seizure activity has not been totally eliminated yet but is almost unobtrusive. We are excited by her progress and feel like we have been given our daughter back, we have hope. It’s got to be worth trying the Ketogenic diet for Uganda particularly as the symptoms of ‘nodding disease’ are worse after eating(carbohydrates?). Google ‘Matthews Friends’ or the ‘Charlie Foundation’ for more information.

  14. #14 Wilbur2
    April 3, 2012

    Just heard an interview on BBC Newshour (4/3/12), Owen Bennet-Jones interviewing Andrea Winkler. The comparison to epilepsy was made, along with suggestions that appropriate drug treatment might be effective. It was mentioned that of the three populations (different areas), the disease might not be precisely the same.

  15. #15 Melissa Morecock
    April 3, 2012

    Ah, BPA. The new vaccine.

    Has anyone studied this disease in relation to thermogenesis? I’ve read articles that state the children begin having cold seizures in cold weather as well.

  16. #16 James
    April 4, 2012

    Has anybody heard of nodding disease being reported among American troops returning from Iraq? The link between Northen Uganda and Southern Sudan on one hand and the USA troops returning from Iraq on the other is that the three have possibly been exposed to weapons that could have left chemicals in the environment that some have think could be the cause of nodding disease.

  17. #17 Nick Smith
    April 5, 2012

    Thanks for this comprehensive summary of events as they stand for this dreadful disease. Imagine the hardship for the parents of these villagers where most of the children are affected and to die.
    The low biotin was an interesting finding, as we know it has brain effects.
    The bacteria transmitted via the fly’s nematode I found particularly interesting(and Wolbachia is a facinating bug). Instead of /or as well as spraying the entire region as they are about to do, to reduce numbers of BlackFly(vector) why not a regular antibiotic regime to remove both the parasite and it’s bacteria. I find no-where PCR testing for the Wolbachia bacteriaPerhaps there is still CSF available (CDC and 2008 had CSF collected.)
    PErhaps the BBB at this age for children allows the transfer of this bacteria.We know they are at more risk of meningitis etc. hmm.

    Other causes one might consider are well mentioned already by you. Perhaps , as many of these received food supplements, it is a toxin in the powdered milk etc or a vaccine problem, but the local govenrments would have sorted that out.Prions in the local meat is an intriguing possibility, enabled by developing brain barrier permeability or a vector.hmm.

    Also often they have exposure to minimal medical inervention such as deworming etc so this may explain some areas no longer having parasites present, but did they HAVE an infestation-of course they did at some time, hence EXPOSURE not concurrent infection is the important question in this disease, again a failure with CDC method if they are seeking a causative agent or vector.
    .
    Perhaps the prandial epileptic effects are from the Release of ante-prandial peptides we now know have CNS effects at the time of degustation.This would explain why it doesnt happen with unfamiliar food.

    The CDC article was inaccurate as there were indeed MRI changes, Gliosis and hippocampal changes in the 2008 study in some children.With all due respect,problems are not solved with such CDC sloppy description of previous studies.

    So , perhaps there is some good in all bad events. Now that internationals want to exploit African resources and control South Sudan, the government money to be put in to keep such people “safe” when surrounded by the local’s dying children. It’s been around since 1960 in the science literature and WHO, but only now the sudden jump to sort it out. Seriously, would you take your children there, knowing those who move there have got the disease?

    Regards, Nick

  18. #18 Kath
    April 6, 2012

    But why is the disease only affecting children and not adults?

  19. #19 Mark Struthers
    April 8, 2012

    Kath’s question is an interesting one. It reminded me of polio outbreaks in the US in the last century where children were much more susceptible to the virus, especially boys? Could a polio like organism be involved in Nodding disease? Perhaps there is a novel synergy between such a microbe and an environmental toxin.

  20. #20 rokujolady
    April 8, 2012

    Wow. I think we’ve pretty much covered all the big-bad-wolves here. American-made weapons, BPA, vaccines, Toxins with a capitol “T”…
    Hey Americans & Western Europeans: get over yourselves. I know it feels really good to flog yourselves about every problem that comes up in the world. It makes you feel all socially conscious and stuff, like you’d never continue the exploits of your colonialist ancestors, but really, THIS IS NOT ABOUT YOU!
    What is so wrong with thinking that this disease is not at all man-made? That there is no environmental component? Why is “environmental component” the first thing that comes up in these discussions?. We don’t come close to understanding the complexities of many of the parasitic organisms out there or their symbiotes, and to say that we’ve discovered, sequenced and studied all the viruses in existence is naive and false. This could be a coinfection, or a prion, or an immune attack on wolbachia.
    It could even have an environmental component. All of these things need to be investigated, but to jump to environmental component straight away because we haven’t seen this before is just silly and at worst arrogant.

  21. #21 justanotheramerican
    April 11, 2012

    Here’s the perspective of someone who lives in Uganda, rather than an American engineer or someone else who might get prickly about environmental toxins being involved:

    http://angeloizama.com/2012/03/01/invisible-children-response-to-nodding-disease-echoes-the-northern-uganda-war-and-more/

    The relationship to conflict and crowded refugee camps is strong there. That is an environment that could spread disease and toxins to a very stressed population in a myriad of ways.
    Why only children…is this developmental with most of the mothers having been exposed to a conflict environment while pregnant?
    As for the food connection, maybe the children’s hunger and excitement when they see food stimulates the seizures.
    Here is a report of one patient responding to epilepsy meds:
    http://in2eastafrica.net/what-it-means-to-suffer-from-nodding-disease/

    I wondered about this being an expression of an autoimmune condition called ‘anti-NMDAR encephalitis’, but the epilepsy component there doesn’t seem to respond to epilepsy drugs, only to immune treatments.

    (Narcolepsy is thought to possibly be autoimmune, too, by the way. Like anti-NMDAR encephalitis it can result after both natural infections and I think more rarely, vaccines. It wasn’t such a stretch for the first Ugandan writer to wonder about a similar mechanism in nodding disease.)

  22. #22 Cassandra
    May 12, 2012

    This is likely a combination of a parasite and a toxic agent that damages the blood-brain barrier so antibodies can cross into the brain. That makes vaccines a very likely culprit in addition to O volvulus or another parasite. This would explain why mainly children are affected. Interestingly, in Uganda where nodding disease first appeared in 2003, it was in the wake of an immunization campaign.

  23. #23 Ross Coe
    Canada
    July 31, 2012

    Africa has been a testing ground for vaccines for decades. Vaccinated under nourished children is contraindicated, but done anyway. Here is the result, a combination narcolespsy, epilepsy. Both conditions are proven vaccine caused.