NIH: Researchers at the National Institutes of Health have uncovered new clues to the link between Nodding syndrome, a devastating form of pediatric epilepsy found in specific areas of east Africa, and a parasitic worm that can cause river blindness. The study, published in Science Translational Medicine, suggests that the mysterious neurological disease may be caused by an autoimmune response to the parasitic proteins. “This study identifies a cause of Nodding syndrome. But more broadly, these findings provide a novel perspective on epilepsy and suggest that some forms of this neurological disorder may be autoimmune in nature,” said Avindra Nath, M.D., clinical director of the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
Nodding syndrome is a form of epilepsy that occurs in children
between the ages of 5 and 16 who live in distinct regions of Tanzania,
Uganda and the Republic of South Sudan. It is characterized by head
nodding, seizures, severe cognitive deterioration and stunted growth.
Nodding syndrome may lead to malnutrition and patients have died through
seizure-associated traumas such as fatal burns and drowning.
Many studies have reported an association between Nodding syndrome and Onchocerca volvulus,
a parasitic worm that can also cause river blindness. The worm is
spread by black flies in specific geographic areas, where clusters of
Nodding syndrome have been observed. However, it was unclear whether the
worm caused this neurological disorder.
In this study, Nath and his colleagues compared serum samples from
patients with Nodding syndrome and healthy controls who all lived in the
same village in Uganda.
The results showed high levels of antibodies to leiomodin-1 in the
samples obtained from patients. In addition, antibody to leiomodin-1 was
also present in cerebrospinal fluid of patients with Nodding syndrome.
Previous studies have shown leiomodin-1 is found in muscles, but this
was the first time researchers saw it in the nervous system.
To confirm that finding, Nath’s team examined brain tissue and found
leiomodin-1 inside brain cells, notably in regions associated with
symptoms of Nodding syndrome. Furthermore, when healthy neurons in a
dish were treated with serum from the patients and antibodies against
leiomodin-1, they did not survive, but removing the antibodies increased
brain cell survival.
“These results may ultimately provide a diagnostic test, which can
help identify individuals at risk for developing Nodding syndrome,” said
Tory Johnson, Ph.D., a post-doctoral fellow in Nath’s lab who conducted
many of the research experiments.
In addition, Nath and his group found that antibodies that bind to leiomodin-1 also attach to proteins from Onchocerca volvulus. Structurally, leiomodin-1 was shown to be very similar to specific proteins from that parasite.
The results of this study suggest that Nodding syndrome may be an
autoimmune disease, in which the immune system incorrectly attacks the
body’s own proteins. According to the researchers, the immune system
creates antibodies to fight off the parasite following infection with Onchocerca volvulus.
However, those antibodies also bind to leiomodin-1, so the immune
system–incorrectly–will attack brain cells that contain that protein,
which can result in symptoms of Nodding syndrome.
“The findings also suggest that therapies targeting the immune system
may be effective treatments against this disorder and possibly other
forms of epilepsy,” said Nath. “Another huge implication of this study
is that exterminating black flies and getting rid of the parasite should
stop the disorder from occurring.”
More research is needed to learn about the role of leiomodin-1 in
healthy people as well as in individuals with epilepsy. For example,
one-third of controls also had leiomodin-1 antibodies, but it is unclear
whether these individuals may eventually develop Nodding syndrome.
Nath’s team is currently developing an animal model of Nodding
syndrome to further study the disease and test potential therapies.
This work was supported by the NIH Intramural Program.
The NINDS is
the nation’s leading funder of research on the brain and nervous
system. The mission of NINDS is to seek fundamental knowledge about the
brain and nervous system and to use that knowledge to reduce the burden
of neurological disease.