Study shows that narcolepsy is an autoimmune disorder

A study claims that narcolepsy is actually an autoimmune disorder which has important impacts for treatment options.

A recent study confirms long-held suspicions that the sleep disorder narcolepsy -- a condition where a person feels uncontrollably sleepy during the daytime and can experience muscle weakness -- is actually an autoimmune disorder. The findings also help to explain why narcolepsy was linked to the Pandemrix H1N1 flu vaccine.

Nearly all people with narcolepsy have a specific genetic signature -- called the HLA signature, where HLA stands for human leukocyte antigens -- but not everyone with this genetic signature goes on to develop narcolepsy (20 percent of the general population is thought to possess this signature). A type of immune cell, called the CD4+ T cell, is associated with this HLA signature; immune cells, like this type of T cell, are responsible for recognizing and eradicating foreign invaders in the body.

Previously, researchers had found evidence to suggest that the immune system was responsible for narcolepsy by attacking neurons that produce a neurotransmitter called hypocretin, which promotes wakefulness. (People with narcolepsy are known to have low levels of hypocretin).

In the new study, published in December in the journal Science Translational Medicine, researchers found that only people with narcolepsy have these CD4+ T cells that react to portions of the hypocretin protein, while people without narcolepsy do not have these T cells. WebMD reported that this discovery was based on examinationof 39 people with narcolepsy, and 35 people without the sleep disorder.

However, Nature News also pointed out that the study did not prove that these T cells themselves kill neurons that produce hypocretin -- there could be something else that's going on causing the death of these neurons.

The researchers also found that CD4+ T cells react strongly to a portion of the H1N1 hemagglutinin protein because it strongly resembles that of two portions of hypocretin -- which could help to explain the link between narcolepsy and the H1N1 Pandemrix vaccine, which actually contained parts of viral protein.

Reuters reported that 900 cases of narcolepsy, if not more, were linked with the Pandemrix vaccine, which was administered in the 2009/2010 flu pandemic in Europe but not the United States. (It is no longer being administered in Europe.)

"The relationship between H1N1 infection, vaccination and narcolepsygave us some very interesting insight into possible causes of the condition," study researcher Dr. Emmanuel Mignot, M.D., Ph.D., a professor of psychiatry and behavioral sciences at Stanford University School of Medicine, as well as director of the Stanford Center for Sleep Sciences and Medicine, said in a statement. "In particular, it strongly suggested to us that T cells of the immune system primed to attack H1N1 can occasionally also cross-react with hypocretin and somehow cause the destruction of hypocretin-producing neurons."

The new findings mean that researchers now have a target to set their sights on -- finding ways to stop the loss of brain cells by the body's own immune system.

"By giving us a new way to think about how neurons in these patients die, it alsosuggests new therapeutic approaches that we would not have considered if we hadn’t learned that this is an autoimmune disease," study researcher Dr. Elizabeth Mellins, M.D., an immunology researcher at Stanford, said in the statement.

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Study: Narcolepsy could be caused by the immune system

According to a recent study, narcolepsy might be caused by an immune system attack, meaning it could be tested for by a blood test, and treatment may center around the immune system.

A new study has uncovered evidence that most cases of narcolepsy are caused by a misguided immune system attack -- something that has been long suspected but unproven.

Experts said the finding, reported Dec. 18 in Science Translational Medicine, could lead to a blood test for the sleep disorder, which can be difficult to diagnose.

It also lays out the possibility that treatments that focus on the immune system could be used against the disease.

"That would be a long way out," said Thomas Roth, director of the Sleep Disorders and Research Center at Henry Ford Hospital, in Detroit.

"If you're a narcolepsy patient now, this isn't going to change your clinical care tomorrow," added Roth, who was not involved in the study.

Still, he said, the findings are "exciting," and advance the understanding of narcolepsy.

Narcolepsy causes a range of symptoms, the most common being excessive sleepiness during the day. But it may be best known for triggering potentially dangerous "sleep attacks." In these, people fall asleep without warning, for anywhere from a few seconds to a few minutes.

About 70 percent of people with narcolepsy have a symptom called cataplexy -- sudden bouts of muscle weakness. That's known as type 1 narcolepsy, and it affects roughly one in 3,000 people, according to the U.S. National Institute of Neurological Disorders and Stroke.

Research shows that those people have low levels of a brain chemical called hypocretin, which helps you stay awake. And experts have believed the deficiency is probably caused by an abnormal immune system attack on the brain cells that produce hypocretin.

"Narcolepsy has been suspected of being an autoimmune disease," said Dr. Elizabeth Mellins, a senior author of the study and an immunology researcher at Stanford University School of Medicine, in California.

"But," she said, "there's never really been proof of immune system activity that's any different from normal activity."

Mellins thinks her team has uncovered "very strong evidence" of just such an underlying problem.

The researchers found that people with narcolepsy have a subgroup of T cells in their blood that react to particular portions of the hypocretin protein -- but narcolepsy-free people do not. T cells are a key part of immune system defenses against infection.

That finding was based on 39 people with type 1 narcolepsy, and 35 people without the disorder -- including four sets of twins in which one twin was affected and the other was not.

It's known that genetic susceptibility plays a role in narcolepsy. And the theory, Mellins explained, is that in people with that inherent risk, certain environmental triggers may cause an autoimmune reaction against the body's own hypocretin.

Infections are the main culprit, and there is already evidence that the H1N1 "swine" flu is one trigger. In China, Mellins noted, there was an upswing in childhood narcolepsy cases after the H1N1 flu pandemic of 2009.

And in 2010, a cluster of narcolepsy cases in Europe was linked to a particular H1N1 vaccine that contained an "adjuvant" designed to induce a stronger immune system response. That vaccine, called Pandemrix, is no longer in use.

All of that led experts to speculate that in some genetically vulnerable people, the H1N1 virus could cause T cells to mistakenly attack hypocretin-producing brain cells.

And in the current study, Mellins's team found that segments of the H1N1 virus were similar to portions of the hypocretin protein -- the same portions that activated narcolepsy patients' T cells. They say that supports the idea that certain infections confuse T cells into attacking hypocretin-producing cells.

An expert on sleep welcomed the new study.

"They're providing more-compelling evidence that this is an autoimmune disease," said Dr. Nathaniel Watson, an associate professor of neurology at the University of Washington in Seattle, and a member of the board of directors for the American Academy of Sleep Medicine.

He and Mellins both said the results could have practical use, too. For one, researchers may be able to develop a blood test to help objectively diagnose narcolepsy.

Right now, Watson said, narcolepsy can be difficult to pinpoint, because the most common symptom -- daytime sleepiness -- has far more common causes. The most common, he noted, is simple: Not going to bed early enough.

So to diagnose narcolepsy, people may have to spend 24 hours in a sleep lab or, in some cases, have a lumbar puncture (spinal tap) to measure hypocretin in the spinal fluid.

Mellins said that if an autoimmune reaction is the cause of type 1 narcolepsy, it might be possible to treat with an immune-suppressing therapy.

The problem, though, is that once people develop full-blown symptoms, their hypocretin-producing cells have already been knocked off.

"We'd need some kind of pre-clinical marker of the disease to be able to intervene," said Watson at the University of Seattle.

Roth of Henry Ford Hospital agreed. "The big challenge is, how will you identify the people to treat?"

Three of the study authors reported they are inventors on a patent to use the hypocretin protein segments to diagnose narcolepsy. Stanford owns the intellectual property rights for this use.

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Autoimmune Epilepsy Clinical Characteristics and Response to Immunotherapy

This is a very interesting article about patients treated with immunotherapy for autoimmune epilepsy.

• Online Features  This Article  • Full text  • PDF  • Author Interview  • eTables and eFigure  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in this journal  Topic Collections  • Neurology  • Epilepsy  • Prognosis/ Outcomes  • Drug Therapy  • Immunologic Disorders  • Immunology, Other  • Alert me on articles by topic  Social Bookmarking          What's this? ONLINE FIRST Autoimmune EpilepsyClinical Characteristics and Response to Immunotherapy Amy M. L. Quek, MBBS; Jeffrey W. Britton, MD; Andrew McKeon, MD; Elson So, MD; Vanda A. Lennon, MD, PhD; Cheolsu Shin, MD; Christopher J. Klein, MD;Robert E. Watson Jr, MD, PhD; Amy L. Kotsenas, MD; Terrence D. Lagerlund, MD; Gregory D. Cascino, MD; Gregory A. Worrell, MD, PhD; Elaine C. Wirrell, MD;Katherine C. Nickels, MD; Allen J. Aksamit, MD; Katherine H. Noe, MD; Sean J. Pittock, MD  Arch Neurol. Published online March 26, 2012. doi:10.1001/archneurol.2011.2985 Objective  To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. Design  Observational, retrospective case series. Setting  Mayo Clinic Health System. Patients  Thirty-two patients with an exclusive (n = 11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more antiepileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset.  Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. Intervention  Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. Main Outcome Measure  Seizure frequency. Results  After a median interval of 17 months (range, 3-72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P < .05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P < .05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone. Conclusion  When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome. Author Affiliations: Departments of Laboratory Medicine and Pathology (Drs Quek, McKeon, Lennon, Klein, and Pittock), Neurology (Drs Britton, McKeon, So, Lennon, Shin, Klein, Lagerlund, Cascino, Worrell, Wirrell, Nickels, Aksamit, and Pittock), Immunology (Dr Lennon), and Radiology (Drs Watson and Kotsenas), Mayo Clinic, College of Medicine, Rochester, Minnesota; and Department of Neurology, Mayo Clinic, College of Medicine, Scottsdale, Arizona (Dr Noe). Abstract here