Narcolepsy

Eating shuts down nerve cells that counter obesity

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Fractions of a second after food hits the mouth, a specialized group of energizing nerve cells in mice shuts down. After the eating stops, the nerve cells spring back into action, scientists report August 18 in Current Biology.  This quick response to eating offers researchers new clues about how the brain drives appetite and may also provide insight into narcolepsy.

orexin in nerve cells

Mouse study offers hints of orexin’s role in weight gain and narcolepsy

These nerve cells have intrigued scientists for years. They produce a molecule called orexin (also known as hypocretin), thought to have a role in appetite. But their bigger claim to fame came when scientists found that these cells were largely missing from the brains of people with narcolepsy.

People with narcolepsy are more likely to be overweight than other people, and this new study may help explain why, says neuroscientist Jerome Siegel of UCLA. These cells may have more subtle roles in regulating food intake in people without narcolepsy, he adds.

Results from earlier studies hinted that orexin-producing nerve cells are appetite stimulators. But the new results suggest the opposite. These cells actually work to keep extra weight off. “Orexin cells are a natural obesity defense mechanism,” says study coauthor Denis Burdakov of the Francis Crick Institute in London. “If they are lost, animals and humans gain weight.”

Mice were allowed to eat normally while researchers eavesdropped on the behavior of their orexin nerve cells.  Within milliseconds of eating, orexin nerve cells shut down and stopped sending signals. This cellular quieting was consistent across foods. Peanut butter, mouse chow, a strawberry milkshake and a calorie-free drink all prompted the same response. “Foods with different flavors and textures had a similar effect, implying that it is to do with the act of eating or drinking, rather than with what is being eaten,” Burdakov says. When the eating ended, the cells once again resumed their activity.

Story continues after graph

Packing it on

Mice in which orexin nerve cells had been killed gained more weight (orange line) than mice that retained those nerve cells (brown line).

J.A. GONZÁLEZ ET AL/CURRENT BIOLOGY 2016

When Burdakov and colleagues used a genetic technique to kill orexin nerve cells, mice ate more food than normal, behavior that led to weight gain, the team found. But a reduced-calorie diet slimmed these mice down.

The results suggest that giving orexin to people who lack it may reduce obesity. But that might not be a good idea. An overactive orexin system has been tied to stress and anxiety, Burdakov says. Orexin’s link to stress raises a different possibility —that anxiety can be reduced by curbing orexin nerve cell activity. “And our study suggests that the act of eating can do just that,” Burdakov says. “This provides a candidate explanation for why people turn to eating at times of anxiety.”

Drug Helps Relieve Disrupted Night time Sleep in Narcolepsy.

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Patients with narcolepsy who have disordered nighttime sleep benefited more from sodium oxybate (SXB) than from modafinil or placebo, according to a randomized trial that documented fewer shifts from sleep stage 2 to 4 or rapid eye movement (REM) to stage 1 or full wakefulness in patients receiving SXB.

“In this retrospective analysis, sodium oxybate appeared to improve polysomnograms and patient-reported measures of disrupted nighttime sleep in narcolepsy,” said Yves Dauvilliers, MD, PhD, from the Reference National Center for Narcolepsy at Gui de Chauliac Hospital in Montpellier, France.

“Disrupted nighttime sleep (DNS) is a clinically common complaint, occurring in almost all patients with narcolepsy,” he said. The important features of DNS are frequent shifts to lighter sleep, awakenings after sleep onset, and poor sleep quality. Researchers retrospectively analyzed data from a randomized trial to evaluate the effects of 3 common narcolepsy treatments.

SXB is approved for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. Polysomnography has suggested that SXB can also increase slow-wave sleep and reduce sleep fragmentation.

“There have been no data, however, related to sleep continuity or patient sleep quality ratings,” Dr. Dauvilliers noted.

The current study, therefore, evaluated the effects of narcolepsy treatment modalities on REM and non-REM sleep-shift changes and sleep quality by retrospective analysis of data from a phase 3 randomized trial.

The findings were presented here at the American Neurological Association (ANA) 2013 Annual Meeting.

Study Details

The study included 278 patients with narcolepsy who were randomly assigned to 1 of 4 treatment groups: SXB, 9 g/day; modafinil, 200 to 600 mg/day; the combination of the 2 agents; or placebo. Patients take 1 dose of SXB before going to sleep and must wake up during the night to take a second dose.

Polysomnograms and sleep quality, as assessed by the Pittsburgh Sleep Quality Index (PSQI)— specifically, question 6 (“During the past month, how would you rate your sleep quality overall?”)—were obtained at baseline and at 8 weeks. The analysis was performed on the 222 patients with evaluable sleep stage and sleep-quality PSQI data.

SXB alone and in combination with modafinil was associated with significant reductions at week 8 in the number of shifts relative to baseline. The reductions with SXB and the combination were greater than those observed with placebo. Modafinil was not associated with any shift stage reductions at week 8, Dr. Dauvilliers reported.

In shifting from stage 2/3/4 REM to stage 1/wake sleep, the median change from baseline was –13.0 (from 40.9 at baseline) in patients receiving SXB alone (P < .001) and –11.5 with the combination (P < .001). No significant reductions in these shifts were observed with modafinil alone or placebo.

In shifting from sleep-stage REM to stage 1/wake, the median change from baseline was –7.0 with SXB alone (P < .001) and –5.0 with the combination (P = .001).

“With SXB, we saw a huge decrease in the number of shift stages and from REM to stage1/wake,” he noted.

Patient-reported sleep quality also significantly improved from baseline with SXB and SXB plus modafinil. The change from baseline was –0.46 with SXB (P < .001) and –0.48 with the combination (P < .001), while modafinil and placebo demonstrated little to no change.

Nausea, vomiting, and dizziness were significantly more common with SXB than with modafinil or placebo, and more treatment discontinuations occurred among patients taking SXB alone or in combination with modafinil.

“SXB improved sleep continuity and sleep quality, and we believe this makes for an improvement in daytime functioning,” Dr. Dauvilliers concluded.

SXB Should Not Be Misused

Session moderator Beth Ann Malow, MD, professor of neurology at Vanderbilt University and director of the Vanderbilt Sleep Disorders Center, Nashville, Tennessee, emphasized that the study was conducted in patients with narcolepsy, and the findings should not be extrapolated to the general population with sleep latency.

“This is an innovative study, looking at this drug in sleep latency, since its traditional use is for improving daytime sleepiness. But it’s important to realize that this is in narcolepsy, not the general population, and this drug has abuse potential,” Dr. Malow said.

“My concern would be that the results are extrapolated to a population where the drug is not FDA [Food and Drug Administration]-approved. We must make this distinction,” she added. “I’m not saying it doesn’t have a role, but we should be careful.”

Comorbidities Common in Narcolepsy.

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Individuals diagnosed with narcolepsy have substantially higher rates of psychiatric and medical conditions than the general population, a new study shows.

“We found that 27% of persons with narcolepsy had a mood disorder, 37% were taking an antidepressant — 3 times higher than the general population — and anxiety disorders were also prevalent,” said Maurice M. Ohayon, MD, DSc, PhD, professor of psychiatry and behavioral sciences at Stanford University School of Medicine, and director of the Stanford University Sleep Epidemiology Research Center in California.

In addition, chronic medical conditions were also greatly increased, said Dr. Ohayon, who noted, “Individuals affected with narcolepsy represent a vulnerable segment of the population. However, we only have a partial understanding of this vulnerability.”

The high prevalence of both medical conditions and psychiatric disorders seen in association with narcolepsy needs to be addressed when developing a treatment plan, Dr. Ohayon concluded.

He presented the findings at the American Neurological Association (ANA) 2013 Annual Meeting here. They were also recently publishedin Sleep Medicine.

High Frequency of Psychiatric Conditions

The study examined psychiatric disorders and medical conditions associated with narcolepsy in 320 narcoleptic patients, who were compared with a sample of 1464 persons matched for age, sex, and body mass index.

Study participants were interviewed regarding sleep habits, health, medication, medical conditions, sleep disorders, and mental disorders using the Sleep-EVAL. Mental disorders were classified according to theDiagnostic and Statistical Manual, 4th edition.

A high proportion of narcoleptic patients reported psychiatric disorders, especially major depressive disorder and social anxiety disorder, which affected nearly 20% of these individuals, Dr. Ohayon reported.

Table. Proportion of Mental Disorders in Narcoleptics vs Matched Controls

Disorder Narcolepsy (%) Controls (%) Adjusted Odds Ratio P Value
Major depressive disorder 17.1 6.4 2.7 <.001
Bipolar disorder 8.5 1.9 4.6 <.001
Post-traumatic stress disorder 11.3 5.3 2.1 <.001
Social anxiety 21.1 8.7 2.4 <.001
Panic disorder 12.5 3.9 3.2 <.001
Agoraphobia 8.5 1.3 6.5 <.001
Simple phobia 5.2 1.3 4.1 <.001
Obsessive-compulsive disorder 3.7 1.0 3.8 <.001
Generalized anxiety disorder 5.5 1.7 3.3 <.001

Five medical diseases were also more frequently observed among narcoleptic participants: hypercholesterolemia, digestive diseases, heart disease, upper respiratory tract disease, and hypertension. The highest odds ratios were for diseases of the digestive system, which were noted in 16.3% of the narcoleptic population vs 5.0% of the controls, a 3-times-increased risk (P < 0.001), and for upper respiratory tract diseases, which were noted for 27.5% and 10.9%, respectively, for an odds ratio of 2.5 (P < 0.001).

“In addition, 34% of narcoleptics were obese, and this was with matching for body mass index in the study, and they are more likely to have hypercholesterolemia and hypertension than the general population,” Dr. Ohayon added.

He said that major depressive disorder mostly developed after the onset of narcolepsy (88%), while social anxiety was present before the onset of narcolepsy in about half the cases. He further noted that several comorbid conditions were autoimmune disorders, such as inflammatory bowel disease, asthma, and allergies.

Dr. Ohayon concluded, “We don’t know how to interpret these data. These are just facts, but we don’t know what they mean.”

Session moderator Louis Ptacek, MD, Howard Hughes Investigator in the Department of Neurology at the University of California, San Francisco School of Medicine, commented on the study for Medscape Medical News.

“The study is quite fascinating, given the statistical significance of the findings,” Dr. Ptacek said. “It’s not surprising that people who might be predisposed to psychiatric disorders could have these precipitated by a stressful event such as narcolepsy, though in some patients the psychiatric diagnosis preceded the narcolepsy. While it’s important to identify these comorbidities, we don’t yet understand the connection or causality yet, as the author pointed out.”

Source: Medscape.com

UK Reverses Swine Flu Vaccine Over Narcolepsy Side-Effect.

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This just in: An example of what happens when people change conclusions based on the data rather than digging in their heels in favor of a pet hypothesis. In this case, the UK government has reversed a previous decision regarding the 2009-2010 European Pandemrix vaccine for “swine flu” and its link to narcolepsy, a sleep disorder that can seriously disrupt activities of daily living. As a result, per The Guardian:

“The Department for Work and Pensions (DWP) has contacted people turned down for compensation last year to explain that, after a review of fresh evidence, it now accepts the vaccine can cause the condition. The move leaves the government open to compensation claims from around 100 people in Britain, and substantial legal fees if a group action drawn up by solicitors is successful.”

According to the Guardian, here’s why the UK is taking this step:

“The government U-turn follows a major study of four- to 18-year-olds by the Health Protection Agency which found that around one in every 55,000 jabs was associated with narcolepsy. A spokesman for (vaccine maker) GSK said it had details of around 900 people from 14 countries who had narcolepsy and were vaccinated.”

Emphasis mine. It’s a good example of drawing new conclusions based on new information, otherwise known as the appropriate conduct of science, and then doing the right thing. A total of 100 people among 6 million who received this vaccination in the UK developed narcolepsy, for an adverse event rate of 0.0017%. The death rate from the “swine flu” in the UK was 0.026%. Put another way, 26 of every 100,000 people who had the flu died; 1.67 people of every 100,000 (1 in every 55,000 according to the study) receiving the vaccine developed narcolepsy. In addition, the vaccine in question evidently was given to groups at high risk for adverse events from contracting the swine flu. The Pandemrix vaccine is no longer in use and was applied for that specific pandemic. One of its ingredients was an adjuvant, intended to enhance the immune response, called ASO3. According to the US Centers for Disease Control and Prevention (CDC), no influenza vaccines licensed in the United States contain adjuvants. The CDC has reviewed US data related to seasonal influenza and H1N1 vaccines used in the US and found no links between any US-licensed vaccine and narcolepsy.

Source: http://www.forbes.com