Since the 1990s, doctors and researchers have puzzled over a specific form of epilepsy that has begun to emerge in clusters of children in South Sudan, Tanzania and Uganda. Without warning, children between the ages of five and 15 would have epileptic seizures that caused them to repeatedly and uncontrollably tilt their heads forward, as if they were nodding. This “buckling syndrome,” as it was called, progresses to devastating neurological degeneration, stunted growth, and in some cases, death. There is no cure and effective treatments can be hard to find in these areas. Sporadic reports of similar cases date back to the 1960s, but for some unknown reason, the syndrome seems to have flared up in recent decades, leading to thousands of estimated cases.
But as the years go by and the number of cases rise, scientists still don’t know what’s behind the mysterious syndrome. Researchers have looked for links to infections, malnutrition, environmental neurotoxins, genetic disorders, or a combination thereof. But they always come up empty handed. The only persistent theory is that the syndrome is somehow related to infections from a parasitic worm called Onchocerca volvulus, which is spread by blackfly bites and causes river blindness. Nodding clusters usually occur in places where the worms are endemic. In addition, researchers have repeatedly found that children with the syndrome are also often infected with the worms.
The problem is that scientists have struggled to find conclusive evidence to support the theory. The worms do not enter the brain or spinal fluid to directly cause seizures, researchers found. And attempts to find evidence that the infection can cause neurological problems indirectly— for example, by triggering a confused autoimmune response that attacks the brain — have also yielded nothing. That is, until now.
A new study, led by Tory Johnson and Avindra Nath of the National Institutes of Health, finally identified a human protein in the blood and spinal fluid of patients with kink syndrome that appears to attack both the worms and neurons in the human brain. In lab tests, the blood protein — an autoantibody — was found to be toxic even to neurons and targeted areas of the brain thought to be damaged by kink syndrome. The finding, published Wednesday in Science Translational Medicine, is solid, long-sought evidence of a connection between the worms and the attacks. And it points out that the terrible condition can be easily averted with anti-parasitic drugs, such as ivermectin.
But the mystery is not over yet. The data, while thorough, isn’t perfect — not all kids with kink syndrome had the autoantibodies. And some healthy people from the same villages did have it.
“The findings from Johnson and colleagues add to the growing evidence that kink syndrome may be caused by O. volvulus infection, but many questions remain as to whether the cross-reactive autoantibodies they identify are pathogenic for this disease,” conclude researchers Robert Colebunders of the University of Antwerp and Maarten Titulaer of the Erasmus University Medical Center in an accompanying editorial.
To find that intriguing (and elusive) autoantibody, Johnson and colleagues had to develop a rigorous test using more than 9,000 human proteins as bait to attack proteins in the patient’s blood serum. Compared to proteins from healthy people, pooled samples from patients with kink syndrome responded 33,000 times more strongly to one human protein called leiomodin-1. This is a protein generally found in smooth muscle and the thyroid, but specifically in the central nervous system and brain, the researchers confirmed.
When the researchers looked at the samples individually, 29 of the 55 patient samples (52.7 percent) had leiodin-1 autoantibodies. Of healthy villagers’ controls, 17 of 55 (30.9 percent) had them, although they were mostly found at lower levels.
The leiomodin-1 autoantibodies could attack worm proteins and were toxic to human neurons in petri dish experiments. In mouse experiments, leiomodin-1 was concentrated in parts of the brain thought to be damaged in kink syndrome and other epilepsy disorders.
To explain why some patients with kink syndrome lacked the autoantibodies, the authors speculate that other antibodies intended to attack the worms also mistakenly harm neurons. “This syndrome is probably not a disease mediated by a single immune specificity,” the authors conclude.
Still, the autoantibody finding doesn’t explain why nodding syndrome has recently flared up. It is also unclear how the autoantibody causes toxicity – leiomodin-1 is found inside neurons, while antibodies usually cause problems by targeting proteins Outside of cells.
Nevertheless, the study by Johnson and colleagues clearly opens up a new avenue of research that may eventually lead to unraveling the pathophysiology of kink syndrome and other forms of epilepsy associated with onchocerciasis. [infections with the worms]conclude Colebunders and Titulaer. “This may ultimately lead to the identification of additional therapeutic options for individuals with this type of epilepsy.”
Science Translational Medicine2017. DOI:10.1126/scitranslmed.aaf6953 (About DOIs).