Between 1990 and 2013, thousands of children in war-torn South Sudan and northern Uganda suddenly developed a severe and puzzling form of epilepsy. When exposed to food or cold temperatures, affected children nodded their heads uncontrollably. Over time the seizures often worsened, leaving the children severely disabled. Many died of malnutrition, accidents, or secondary infections.
In some communities, roughly half of families had at least one child with the condition, called nodding syndrome; by 2013, an estimated 1600 children in Uganda were affected. But the cause of the devastation was a mystery. Now, a study finds that a parasitic worm often found in the children might trigger the body’s own defenses to attack neurons.
The study doesn’t prove the worm is the culprit, but it “is the first to show that a cause-effect relationship is plausible,” says Hermann Feldmeier, a parasitologist at the Charité University Hospital in Berlin, who was not involved in the study.
The rash of cases in Uganda and South Sudan triggered an intense hunt for the cause, but searches for viruses, bacteria, environmental toxins, genetic factors, and nutritional deficits all came up empty. One key clue: Areas with nodding syndrome also had high rates of onchocerciasis, an infection with the parasitic worm Onchocerca volvulus. Spread through the bites of black flies, which breed in swift-flowing streams, the worms can invade the eye, and the infection is commonly known as river blindness. The World Health Organization estimates that at least 18 million people, most in sub-Saharan Africa, are infected.
Researchers had suggested as early as the 1960s that high rates of epilepsy in Tanzania, with similar nodding symptoms, might be related to onchocerciasis. Others have noted that children with nodding syndrome are more likely to be infected than their healthy peers. But there’s no evidence that the worm invades the brain or directly causes seizures.
Some researchers suggested that the worm instead causes an autoimmune reaction that damages the nervous system. Searches for antibodies that might play an autoimmune role had come up empty. But neuroimmunologists Avindra Nath and Tory Johnson of the National Institutes of Health in Bethesda, Maryland, decided to use an improved protein chip to screen for antibodies to thousands of proteins at once.
The new tool proved its worth. Blood from nodding syndrome patients reacted strongly to four proteins; in the case of one protein, called leiomodin-1, patient sera reacted 33,000 times more strongly than did sera from unaffected controls. The researchers then looked for the antibodies causing the reaction. As they report this week in Science Translational Medicine, antibodies to leiomodin-1 turned up in 29 of 55 nodding syndrome patients but only 17 of 55 controls. Patients also carried much higher antibody levels than controls.
Leiomodin-1, which likely plays a role in cell shape, is found in smooth muscle and thyroid cells. Johnson’s team showed that it is expressed in the nervous system and brain, too. They also found a clue to what might trigger an autoimmune reaction to the protein: Several O. volvulus proteins resemble it. After the immune system gears up to fight the worm, similarities between an O. volvulus protein and leiomodin-1 may cause the antibodies to mistakenly attack neurons.
The study gives little hope to children already affected, Nath says. Although antiseizure drugs can help, if the immune system has attacked neurons, the damage is likely permanent. However, the work could suggest a straightforward way to eliminate the disease, says infectious disease specialist Robert Colebunders of the University of Antwerp in Belgium, because the drug ivermectin kills the worm. Existing campaigns to eliminate river blindness by giving the drug could have a collateral benefit: After the Ugandan government stepped up ivermectin treatment, new cases of nodding syndrome plunged to nearly zero, Colebunders says. “If you eliminate the onchocerciasis, the epilepsy really disappears.”
Yet the link between the worm and nodding syndrome doesn’t explain why the illness suddenly appeared in a region where onchocerciasis has likely been common for centuries, or why nodding syndrome only affects children and youth. Johnson, now at Johns Hopkins University in Baltimore, Maryland, says malnutrition, exposure to other diseases, or genetic variation in how the body makes antibodies may also play a role. Other researchers have suggested that measles infection followed by malnutrition could trigger the disease.
Neurologist Erich Schmutzhard of the Medical University of Innsbruck in Austria has other doubts. He says that the leiomodin-1 antibodies could be a result of epilepsy, not its cause. The protein seems to be on the inside of neurons, not the outside, he notes. Seizures kill neurons, and he speculates that dying neurons could spill the protein into the blood stream, triggering the antibodies.
The onchocerciasis connection is intriguing but far from definitive, says neurologist Andrea Winkler of the Technical University of Munich in Germany. She, too, thinks the syndrome is likely caused by multiple factors, such as malnutrition, parasites, and viruses like measles. “There are still lots of links missing.”