An unusual increase in narcolepsy cases in Europe was linked to a new flu vaccine used there, and now researchers may have figured out why: A protein in the vaccine appears to mimic one in the brain that plays a role in the sleep disorder.

People with narcolepsy experience severe daytime sleepiness and "sleep attacks," in which they suddenly fall asleep for a short time. The vaccine that was linked to the disorder was used in 2009 and 2010 to protect against the H1N1 strain of flu, which is sometimes called the swine flu.

The new findings also suggest that the immune system may play a role in the disorder, and that in rare cases vaccines or infections can trigger narcolepsy in people with a certain genetic mutation.

Still, the researchers emphasized that the risk of getting narcolepsy from the vaccine is extremely small, and that "the benefits of influenza vaccination currently far outweigh the risks of complications," they said.

What's more, for people who are genetically predisposed to narcolepsy, the risk of developing the disorder may be higher if they become naturally infected with the flu rather than getting the vaccine to protect against it, the researchers said.

Previous studies linked this version of the swine flu vaccine, called Pandemrix (made by GlaxoSmithKline), and cases of narcolepsy. For example, a study in England found that children who had narcolepsy were 14 times more likely to have been vaccinated with Pandemrix than other children in England of the same age.

In another study, researchers estimated that the chances of developing narcolepsy following vaccination in Finland and the United Kingdom were between 1 in 16,000 and 1 in 50,000. After the 2009 to 2010 swine flu outbreak, Pandemrix was withdrawn from the market.

Other versions of the swine flu vaccine havenot been linked with an increased risk of narcolepsy. [6 Flu Vaccine Myths]

In the new study, the researchers compared components of the Pandemrix vaccine with those of another H1N1 vaccine, called Focetria, which was manufactured by Novartis.

They found that part of a viral protein in the Pandemrix vaccine mimicked the structure of a brain receptor that binds to a hormone called hypocretin. This hormone is involved in keeping people awake, and people with narcolepsy have lower levels of hypocretin, which led the researchers to hypothesize that problems with hypocretin or its receptor could play a role in the sleep disorder.

In contrast to the Pandemrix vaccine, the Focetria vaccine contained much lower levels of the viral protein that mimicked the hypocretin receptor.

Next, the researchers analyzed blood samples from 20 people in Finland who developed narcolepsy after Pandemrix vaccination, and found that these people had antibodies in their blood that bound to the H1N1 virus and also to the hypocretin receptor. But people who received the Focetria vaccines did not have these antibodies.

The researchers speculate that, in people who are already predisposed to narcolepsy because of a genetic mutation, receiving the Pandemrix vaccination triggered an autoimmune response — these patients developed antibodies that not only attacked the virus, but also attacked the hypocretin receptor in the brain.

This could interfere with the brain signaling of hypocretin, leading to narcolepsy, said study researcher Dr. Lawrence Steinman, a professor of pediatrics and of neurology at Stanford University School of Medicine.

However, the researchers still need to prove that these antibodies against the hypocretin receptor do indeed get into the brain. This will be the next step in the research, Steinman said.

"This paper is really elegant, and establishes a mechanism for how this one specific pandemic flu vaccine may have caused narcolepsy in some patients," said Dr. Amesh Adalja, an infectious-disease specialist and a senior associate at the University of Pittsburgh Medical Center's Center for Health Security, who was not involved in the study.

Although more work is needed to confirm the findings, "it seems to me, that this really is a likely explanation, based upon all these steps the researchers took to prove this hypothesis," Adalja said. He noted that the researchers had genetic evidence, as well as evidence from patients' blood, which both pointed to the same mechanism.

Steinman noted that people who are infected with the flu appear to generate higher levels of antibodies to this viral protein, compared with people who are vaccinated with Pandemrix. "Therefore, there is potentially far greater risk of getting narcolepsy with influenza infection compared to influenza vaccination in those genetically susceptible to narcolepsy," Steinman said.

The flu has been linked with other sleeping disorders. For example, after the epidemic of Spanish flu in 1918, there was an increase in people suffering a "sleeping sickness" known as encephalitis lethargica. (Patients with this condition were the subject of the 1973 book "Awakenings.")

In the new paper, the researchers speculate that, because the 1918 flu strain also contained this "mimic" viral protein, an autoimmune reaction might also explain the rise in encephalitis lethargica after the Spanish flu.

The study is published today (July 1) in the journal Science Translational Medicine.                                 

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