Since the 1990s, doctors and researchers have puzzled over a distinct form of epilepsy that started popping up in clusters of kids across South Sudan, Tanzania, and Uganda. Without warning, kids between five and 15 years old would begin having seizures that cause them to repeatedly and uncontrollably tilt their head forward—as if they’re nodding. This "nodding syndrome," as it was dubbed, progresses to devastating neurological degeneration, stunted growth, and in some cases death. There’s no cure and effective treatments can be hard to come by in these locales. Sporadic reports of similar cases date back to the 1960s, but for some unknown reason the syndrome seems to have flared in the past few decades, leading to thousands of estimated cases.

Yet, as years go by and case numbers rise, scientists still don’t know what’s behind the mysterious syndrome. Researchers have looked for ties to infections, malnutrition, environmental neurotoxins, genetic disorders, or some mix of some of those. But they’ve always come up empty-handed. The only persisting theory is that the syndrome is somehow linked to infections of a parasitic worm, called Onchocerca volvulus, which is spread through bites from black flies and causes river blindness. Nodding clusters tend to occur in places where the worms are endemic. Plus, researchers have repeatedly found that kids with the syndrome also tend to be infected with the worms.

The trouble is scientists have struggled to find conclusive evidence to support the theory. The worms don’t invade the brain or spinal fluid to spark seizures directly, researchers found. And efforts to find evidence that the infection might trigger neurological problems indirectly—such as by inciting a haywire autoimmune response that attacks the brain—have also turned up nothing. That is, until now.

A new study, led by Tory Johnson and Avindra Nath at the National Institutes of Health, finally identified a human protein in the blood and spinal fluid of nodding syndrome patients that seems to attack both the worms and neurons in the human brain. In fact, in lab tests the blood protein—an auto-antibody—appeared toxic to neurons and targeted parts of the brain thought to be damaged by nodding syndrome. The finding, published Wednesday in Science Translational Medicine, is solid, long-sought evidence of a connection between the worms and the seizures. And it hints that the terrible disorder could be easily averted with anti-parasitic drugs, such as ivermectin.

But, the mystery isn’t over. The data, while thorough, isn’t perfect—not all of the kids with nodding syndrome had the auto-antibodies. And some healthy people from the same villages did have it.

“The findings of Johnson and colleagues add to the growing evidence that nodding syndrome may be triggered by O. volvulus infection, but many questions remain regarding whether the cross-reactive autoantibodies they identify are pathogenic in this disease,” researchers Robert Colebunders of the University of Antwerp, and Maarten Titulaer of Erasmus University Medical Center, conclude in an accompanying editorial.

Cloudy clue

To find that intriguing (and elusive) auto-antibody, Johnson and colleagues had to develop a sweeping assay using more than 9,000 human proteins as bait for assaulting proteins in the patients’ blood serum. Compared with proteins from healthy people, pooled samples from nodding syndrome patients reacted 33,000 times more strongly to one human protein called leiomodin-1. This is a protein found generally in smooth muscle tissue and the thyroid, but specifically in the central nervous system and the brain, the researchers confirmed.

When the researchers looked at samples individually, 29 of 55 patient samples (52.7 percent) had leiomodin-1 auto-antibodies. Of the healthy villager controls, 17 of 55 (30.9 percent) had them—though they tended to be found at lower levels.

The leiomodin-1 auto-antibodies could attack worm proteins and were toxic to human neurons in petri-dish experiments. In mouse experiments, leiomodin-1 was concentrated in areas of the brain thought to be damaged in nodding syndrome and other epilepsy disorders.

To explain why some nodding syndrome patients didn’t have the auto-antibodies, the authors speculate that other antibodies intended to attack the worms also mistakenly hurt neurons. “This syndrome is likely not a disease mediated by a single immune specificity,” the authors conclude.

Still, the auto-antibody finding doesn’t explain why nodding syndrome has flared recently. Also, it’s unclear how the auto-antibody causes toxicity— leiomodin-1 is found inside neurons, while antibodies usually cause trouble by targeting proteins outside of cells.

Nevertheless, “the study by Johnson and colleagues clearly opens a new research direction that ultimately may lead to the unraveling of the patho-physiology of nodding syndrome and other forms of epilepsy associated with onchocerciasis [infections with the worms]," Colebunders and Titulaer conclude. “This may ultimately lead to the identification of additional therapeutic options for individuals with these types of epilepsy.”

Science Translational Medicine, 2017. DOI:10.1126/scitranslmed.aaf6953 (About DOIs).