A disease mystery with no shortage of leads now has an intriguing new one. Since the 1960s, thousands of children in poor, war-torn regions of East Africa have developed epilepsy-like seizures in which their heads bob to their chest; over time, the seizures worsen, cognitive problems develop, and the victims ultimately die. Researchers have proposed causes for nodding syndrome that include malnutrition, parasites, and viruses, but have not proved a clear link to any of them. Now, the first published examination of the brains of children who died after developing the condition suggests it has a key similarity to certain brain diseases of old age, such as Alzheimer's and Parkinson's: It leaves victims' brains riddled with fibrous tangles containing a protein called tau.
"Nodding syndrome is a tauopathy," concludes Michael Pollanen, a pathologist at the University of Toronto in Canada who is lead author of a report published last month in Acta Neuropathologica. Pollanen believes the finding "suggests a totally new line of investigation" into the syndrome. As significant as the discovery of the tangles may be what his group of Canadian and Ugandan researchers didn't find: any sign of the brain inflammation that might be triggered by a parasite or virus. "Our hypothesis is that nodding syndrome is a neurodegenerative disease, like Alzheimer's," Pollanen says.
Some who study the condition are skeptical, but the possibility excites researchers working on other tauopathies including Alzheimer's. Childhood forms of those diseases are exceedingly rare, but the nodding syndrome finding "means [tau deposition] is not an age-dependent problem," says John Hardy, of the UK Dementia Research Institute at University College London. Something else must have triggered the tauopathy in these children. And because nodding syndrome struck a small region of East Africa, over a specific time period—in Uganda, the condition appears to be vanishing—its trigger might be relatively easy to identify, and could shed light on the causes of diseases like Alzheimer's, Hardy and others say.
First, though, the researchers need to convince others who have studied nodding syndrome for years that they are right. Originally reported in Tanzania, the disease spread to what is now South Sudan in the 1990s and to northern Uganda after 1998. Uganda has reported 3000 cases, but no new ones since 2014. The current study was done on the brains of five Ugandan children who fell ill while living in camps for internally displaced persons between 2005 and 2010, when Joseph Kony's Lord's Resistance Army was terrorizing the region, and later died.
The brains are among a dozen obtained by U.S. and Ugandan researchers between 2014 and 2017, overcoming challenges such as persuading relatives, harvesting the organs promptly after death, and transporting them from remote areas in a tropical climate. Initial investigations done in the United States were never published—it's not clear why—and the brains were returned to Uganda, where Pollanen's group studied all 12. They hope to publish their analyses of the remaining seven soon.
The current paper is thin on detail and lacks important controls, cautions neurologist Avindra Nath of the U.S. National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who has studied nodding syndrome. It does not describe the brain pathology in children from the same population who died of other forms of epilepsy, for example.
Robert Colebunders, an infectious disease expert at the University of Antwerp in Belgium who has long worked on nodding syndrome, says he has still-unpublished postmortem findings from seven children who fell ill at the same time, in the same camps, but survived longer because they received better care and experienced fewer seizures. None of them shows tauopathy, he says. "My conclusion is that tau [deposition] is a consequence of seizures, not a cause."
Colebunders favors a long-standing theory that the ultimate cause of nodding syndrome is infection by a parasitic worm called Onchocerca volvulus, which is endemic to the same regions. There is no evidence that the worm itself penetrates the brain, but last year, Nath and others proposed that a protein in the worm triggers the production of antibodies that attack a similar protein on neurons, in a misdirected autoimmune response.
It's dangerous to propose that nodding syndrome is a neurodegenerative disease, Colebunders says, because it could divert resources away from much-needed efforts to eradicate the worm and to improve care for children with the illness. "With good care and nutrition, the epilepsy can be controlled and the children can go back to school without suffering any cognitive deficit," he says.
But Peter Spencer, a neurotoxicologist at Oregon Health & Science University in Portland, suspects the worm is a bystander. He suggests it opportunistically infects people who have another condition that also triggers seizures and tau deposition. How it all fits together is unclear, but tau gives investigators one more piece of the puzzle, Spencer says. "We have an opportunity here to discover the primary cause of this disease, and then to do primary prevention." Not only will that benefit affected children, Spencer adds, "It will potentially open up our understanding of other tauopathies, too."