But a team of American and Indian scientists say they have found the cause of the mystery illness, which killed more than 100 children a year: eating unripe lychees on an empty stomach.
Turns out children with the brain illness were nearly 10 times more likely to have eaten lychee, and 6 times as likely to have visited a fruit orchard, in the 24 hours before they became ill compared with the healthy kids. Hundreds are admitted to hospital from around mid-May, peaking in June, with seizures and swelling on the brain after waking up in the night screaming. "This is the first confirmation that this recurring outbreak in Muzaffarpur is associated with litchi consumption and both hypoglycin A and MCPG toxicity", wrote the researchers.
In 2013, the U.S. Centers for Disease Control and Prevention (CDC) and the National Centre for Disease Control, India (NCDC) initiated an investigation into the mysterious outbreak using hospital-based clinical surveillance, an epidemiological case-control study and extensive laboratory testing.
In a new study published in The Lancet Global Health, researchers analyzed nearly 400 cases of children who developed the illness in 2014 and compared them to 100 children who didn't have it.
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The hungry children - many of whom were malnourished - are thought to have gorged themselves on fruit that fell from the trees in the commercial orchards during the lychee season, consuming the toxin, which inhibits the body's ability to produce glucose.
Low blood sugar levels: Some children had extremely low levels of glucose, which meant they were twice as likely to die. What's more, the study of urine samples showed that two-thirds of the sick children had an indication of exposure to two toxins found in lychee seeds called Hypoglycin and Methylenecyclopropyl glycine.
In the study, the parents reported that their kids would often frequent the neighbouring orchards and eat lychee fruit. Unripe ackee fruit was known for decades to cause "Jamaican vomiting sickness", but that knowledge did not reach certain places like Muzaffarpur until now, noted Oregon Health and Science University's Peter Spencer, professor of neurology and Valerie Palmer, senior research associate, in a comment published alongside the paper.
Residents in affected areas are being advised to look after children to ensure minimized consumption of the lychee fruit. Hypoglycin A and methylenecyclopropylglycine (MPCG) are toxins naturally found in litchis.
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The second clue: Most of the victims had very low blood sugar levels.
The number of reported cases per year dropped to less than 50 from hundreds, The New York Times added. The litchi lovers young children would spend the day playing and feasting on litchis and sleep without dinner, this seemingly normal eating habit led to the most unimaginable catastrophe.
However, the researchers said there are still some questions surrounding the mystery.
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