10 years ago my co-blogger Delayed2Sleep started this blog to bring awareness of Delayed Sleep Phase Syndrome. I joined as co-blogger 5 years ago under the name LivingWithN24. We both have continued to blog about issues affecting people with both DSPS and Non-24-Hour Sleep-Wake Cycle Disorder (N24).
I have been very gratified at the number of people online who have told us how this blog has helped them. For example several people have told me that the post on Charting the Course of N24 helped them make a sleep chart and get a diagnosis. Others have said that the Melatonin: Less is Sometimes More post has helped them find a dose that finally helps their sleep cycle.
Today is N24 Awareness Day. It is a day set aside by the online N24 community to help spread awareness of this condition. This is the third annual N24 Day.
In going online at the DSPS blog to write up something for today, I realized I had not posted anything here since last N24 Day. I had a twinge of guilt, but that soon went away. I may not have blogged much this year but I have done quite a lot this year concerning N24 and circadian disorders, some of it on my own and some as Vice-President of the Circadian Sleep Disorders Network.
I hope to blog here more in the future but in the meanwhile I thought I’d use this post to update the readers on what I have been doing in the world of N24 and circadian disorders generally. Some of the readers may already know about this, but many may not and for them I have a lot of useful links and information to share.
But first a word about N24 Awareness Day. The theme for this year is “Think Zebras!” This comes from a saying taught to doctors “When you hear hoof beats, think horses, not Zebras.” This means when faced with symptoms look for a common cause not a rare one. The patient with a cough, fever and muscle aches is more likely to have flu than Q fever.
But this approach leaves people with rare disorders out in the cold. Those of us with N24 truly are Zebras, and diagnosticians need to keep that in mind. I have said more about this in my post on the CSD-N site, so rather than repeat myself I will give you a link (and while you are there consider joining. It is a worthy cause.)
So what else has happened in the world of N24 since the last N24 Awareness Day? Well a few things…
I was honored this year to be asked to write an article on N24 for the journal Sleep Review. I should thank Ed Grandi for connecting us, and Sree Roy, the Editor of Sleep Review, for her hard work. The article is called “What You Need to Know about Non-24”. It is published online and in digital and paper formats.
I have been very gratified by the reception of the article by both patients and health professionals. A friend recently told me it turned up in the waiting room of her sleep clinic. So word is getting around about N24.
(This was my second formal article on N24. The first, which I don’t think I have linked to on this blog, is a report on N24 for the National Organization of Rare Disorders, which I co-authored with Dr. Katherine Sharkey a couple of years ago: http://rarediseases.org/rare-diseases/non-24-hour-sleep-wake-disorder/)
Another high point of the year was participating in an online course offered by Coursera called Circadian Clocks – How Rhythms Structure Life. It was taught by two eminent circadian researchers, Martha Merrow and Til Roenneberg of Ludwig-Maximilians-Universität München. I am not sure if the course will be offered again, but if you have a serious interest in circadian rhythms I highly recommend it.
Finally, another major event this year was the publication of new guidelines for the treatment of circadian disorders by the American Academy of Sleep Medicine.
A preliminary version of the guidelines was released earlier and interested parties were asked to comment. The deadline for comments was very tight. CSD-N submitted comments on the guidelines. In addition to helping compose the CSD-N comments I also submitted additional comments of my own which we did not have time to incorporate into the official CSD-N comments.
The most important aspect of the AASM guidelines — both their strength and weakness — is that they are based on a strict interpretation of the concept of evidence-based medicine. According to this approach only treatments which have been subjected to controlled clinical trials are given a recommendation. And clinical trials have to meet a number of strict criteria to be counted.
This is often a useful constraint. It avoids the recommendation of treatments which are ineffective. It is particularly useful in the case of common disorders where clinical trials can be organized. (To give an example from personal experience, I recently suffered a bout of diverticulitis. Antibiotics are often prescribed for this condition but at least 5 controlled trials have demonstrated that they make absolutely no difference in outcome.)
However, in the case of rare disorders such as N24, this restriction can be both a blessing and a curse. Given the rarity of sighted N24s there are very few clinical trials, and those that have been done did not meet the criteria of the AASM. Thus the guidelines give “no recommendation” for any treatment of sighted N24. For N24 in the blind, melatonin agonists are given a “weak for” recommendation.
The good side of this is it amply demonstrates the urgent need for more studies of treatments for N24, particularly in sighted patients. It is intolerable that there is no validated treatment for such a devastating disorder.
The bad side of this approach is that it discounts evidence such as case reports of the efficacy (albeit partial and with limitations) of treatments for sighted N24, in particular light/dark therapy or combinations of light/dark therapy with melatonin. In the absence of clinical trials for a rare disorder, case reports may be better than no evidence at all. Nevertheless it is true that in the absence of controlled trials we don’t know how effective such treatments are for sighted N24s as a whole. This is an issue I may discuss more in the future.
So that has been my past year of involvement with N24 awareness. In summary, there is more attention being paid to this condition. But we still have a long way to go. We need better understanding of the underlying biology of N24 — which is still poorly understood — and we need validated treatments.
— LivingWithN24 (James Fadden)
The WordPress.com stats helpers prepared a 2014 annual report for this blog about Circadian Rhythm Disorders (CRDs).
Here’s an excerpt:
The concert hall at the Sydney Opera House holds 2,700 people. This blog was viewed about 23,000 times in 2014. If it were a concert at Sydney Opera House, it would take about 9 sold-out performances for that many people to see it.
Tags: N24, N24 Awareness Day, Non-24, Tasimelteon
Well, it’s that time of year again. The nip of Autumn is in the air, and that can mean only one thing, N24 Awareness Day. Just one year ago, the N24 community celebrated the first N24 Day, having designated November 24th as our day to spread awareness of the condition.
2014 has certainly been an eventful year for awareness of N24. In January of this year the US Food and Drug Administration approved the first drug specifically designated for the treatment of N24 in totally blind patients. In the US, advertising of medicines is permitted and Vanda has been running advertisements on television and radio talking about N24. A year ago the average person had never heard of N24. Now, if you were to ask someone (at least in the US) if they had heard of N24 there is a good chance the answer would be yes, because of the Vanda campaign.
But awareness does not necessarily mean understanding. Unfortunately as awareness has spread, so have a number of myths and misconceptions about N24. People with N24 I have talked to tell me of the reactions that they now get which reflect these myths. It is worth addressing this issue.
Myth #1: “N24 only happens to blind persons”.
Vanda’s Non-24 campaign has particularly talked about blind persons since that is the population for which the drug is approved. It is true that if you are blind your chance of having N24 increases dramatically. Over 50% of totally blind persons will have N24. It is a serious condition — many blind persons have even said it is the worst part about being blind.
But N24 also occurs in sighted persons. I am sighted myself, and so are many other people with N24 that I know. There are many research articles on the condition and it is agreed that it does occur in individuals who have sight.
In the case of blind persons, the cause of N24 is the absence of light as a zeitgeber to regulate the circadian clock. This is not usually the issue with sighted persons. In sighted N24 the cause is a more complex dis-regulation of the body’s circadian system and sleep wake cycle. Although blind and sighted N24 share the same diagnostic name, the biology is quite different.
The rate of occurrence of N24 among sighted persons is much smaller than among the blind, but there are also many more sighted people overall. We don’t really have a good estimate of the total number of sighted N24s. We can put a lower bound. There are about 100 case reports in the medical literature. And online support groups number in the low hundreds. This is still a small percent of the population, but sighted N24 does exist.
Myth #2: “N24 is a disease invented by drug companies”
It is understandable that the average person, never having heard of this somewhat exotic condition, and suddenly deluged with paid advertising might think this condition was concocted for profit. One person with N24 told me her social services worker said, “Oh, N24, that’s that disease that no one really has.”
Nothing could be farther from the truth. Anyone who thinks that is the case needs to talk to the many persons who have suffered for years with this awful condition.
In my own case, I first developed N24 in 1982. I doubt I was influenced by a drug ad 30 years in the future. I was first diagnosed in 1992 at the National Institutes of Health. They didn’t just take my word for it. They conducted a 2 year study, with round-the-clock monitoring of blood chemicals via an IV line and a slew of other medical tests. This is a real condition due to a disorder of the biological clock and the regulation of the sleep-wake cycle.
There are many others who have endured this condition. You can read some personal accounts at the CSD-N web site under “personal stories”.
Bottom line: N24 is real and the suffering it causes is real.
Myth #3: “You can just take a pill and fix your N24”.
Again, this is an understandable reaction to a drug company campaign. But the reality is more complicated.
Let’s first deal with blind persons, the target population for the new drug Hetlioz. The most straightforward way to measure response to an N24 treatment is the percent who achieve entrainment. Entrainment does not mean everything is fixed, you can still have major symptoms such as debilitating exhaustion, but lack of entrainment does really mean treatment has not worked.
In the case of Hetlioz about 20% of patients achieved entrainment after 1 month of treatment. After 7 months this rose to to 59% although that figure does not include those who dropped out of the trial or whose period was not measured at 7 months. When all subjects are included, the percent of those who started the trial and achieved both entrainment and reduced symptoms at 1 or 7 months was only 28.9% (1). So success is by no means guaranteed and treatment can take a long time to achieve results.
This isn’t meant to single out Hetlioz for criticism. It may be a useful drug for some and I am glad it is available. Melatonin is also effective in many cases of blind N24. But neither is anything close to 100% successful for blind patients. The point is not that Hetlioz is an ineffective drug, because it does help a percentage of sufferers. The point is that N24 is hard to treat.
We don’t yet have data on Hetlioz in sighted N24s. The biology of sighted N24 suggests that melatonin and melatonin agonists such as Hetlioz may be of less use than in blind subjects. The prolonged intrinsic period of some N24s may be outside the range of entrainment by melatonin-like drugs. In practice, while some sighted N24s respond to melatonin and related drugs, most do not (2). Whether this will be any different with Hetlioz remains to be seen.
Of course sighted N24s have some treatment options not available to totally blind persons, namely light and dark therapy. These treatments can be successful in some cases, but not all. And the light/dark regimens are complicated and time consuming. Nor does this approach correct the underlying cause of the disorder. It is a symptomatic, not a curative treatment. Even when light entrainment works patients may be left with substantial residual symptoms such as tiredness or a split sleep schedule. I am known for strongly encouraging people to try light/dark treatment, but it is not a panacea.
All of this is a far cry from popping a pill to fix the disorder.
Those are three of the myths I have heard circulating in the past year. It has changed my perspective on how to approach N24 in discussions with medical professionals and the public. In the past when I told them I had N24 (or hypernycthemeral syndrome as it used to be called) I was greeted with a blank stare or “what is that?…can you spell it?” The reaction might be skeptical. On the other hand I was dealing with a blank slate and could tell them about the condition if they were willing to listen.
Now the situation for those of us with N24 is different. The good news is, people now may have heard of the condition. The bad news is, what they think they know about the disorder may not be the truth. In the words of Mark Twain, “It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so”
With this new awareness, are we better off or not? I’m not sure. What do you think?
–posted by LivingWithN24
This post also appears on the CSD-N web site where you can find out more about N24 and other circadian disorders.
1. Marlene Dressman PhD. Clinical Program Efficacy. Tasimelteon, as presented to the FDA Peripheral and Central Nervous System Drugs Advisory Committee November 14, 2013 Silver Spring, MD slides CE-79 and CE-81
2.Kamei Y, Hayakawa T, Urata J, Uchiyama M, Shibui K, Kim K, Kudo Y, Okawa M. Melatonin treatment for circadian rhythm sleep disorders. Psychiatry Clin Neurosci. 2000 Jun;54(3):381-2.
Tags: Guest blogger, Non-24
Perhaps I’ve “arrived”, when Healthline.com approaches me with an offer of a guest post? I said yes, please. So here is the article by their health-and-fitness writer Adrienne:
Thank you Healthline and Adrienne, for the timely article! —D
Non-24 — Not Just a Disorder of the Blind
Non-24-Hour Sleep-Wake Disorder is not a condition that a lot of people were aware of, at least until the first medication for it was approved by the U.S. Food and Drug Administration earlier this year. The advertising for Vanda Pharmaceuticals’ new drug has brought some attention to the disorder, but since the drug is aimed at (and only approved for) those who are blind, few realize that the disorder can and does affect sighted people as well.
Non-24 in Layman’s Terms
Non-24 is a circadian rhythm sleep disorder that causes people to be unable to adjust their sleep-wake cycles to a 24 hour day. This causes their sleep time to progress around the clock. To put it more simply: Each night people who have Non-24 go to sleep later than the night before, each time sleeping in the next day in accordance with the time they went to bed. They go to bed later and later every day, eventually ending back at the same bedtime and starting the cycle all over again. As you can imagine, this doesn’t only interfere with day-to-day responsibilities, but it can also lead to daytime sleepiness, memory issues, depression and more.
Non-24 in the Sighted
In a majority of totally blind people, Non-24 is the result of their inability to perceive light; the lack of light interferes with synchronization of their internal clocks to the day/night cycle in nature. Even though the disorder goes by the same name for the sighted as it does for the blind, the causes are entirely different. Though it’s not currently known just how many sighted people have Non-24, there are several known causes of it.
Here are some of them:
- Changes in light sensitivity. In some sighted people, even though they are able to see well and appear to have great vision, daily light signals may not get through properly, leading to disrupted circadian rhythms.
- Melatonin imbalance. Melatonin, a hormone, plays a part in linking sleep to the day-night cycle. Some sighted people with Non-24 have been found to produce less melatonin than normal while others produce too much. Problems with metabolizing melatonin properly can also impair circadian rhythm and cause Non-24.
- Trauma and physical damage to the brain. Healthy people who suffer head injury can develop Non-24 when the injury damages the circadian and sleep centers of the brain. This can also be the case with brain tumors, such as craniopharyngiomas. For some it’s the brain tumor itself that causes the damage while for others it can be the effect of treatment, such as radiation.
- Environmental factors. Sometimes it’s a sighted person’s exposure to light, or the lack of it, that can interfere with the ability to maintain a 24-hour sleep-wake cycle. An example of this, in scientific studies in the laboratory, is being in an isolated environment without access any clues as to what time of the day it is, and not being allowed to turn lights on or off as desired. In such studies healthy people will temporarily acquire a non-24 sleep pattern, though, of course, not the disorder.
- Individual sleep patterns. According to The National Organization for Rare Disorders (NORD), a person’s need for sleep could lead to a Non-24 sleep cycle. They give the example of a healthy person who may sleep 8 hours and stay awake for 16 while another person may need 12 hours of sleep but still be awake for the normal 16 hours, leading to a 28-hour day. The same can happen for a person who sleeps the normal 8 hours but then requires 20 hours of awake time before sleep again is possible, also leading to a 28-hour day.
These are just some of the known or suspected causes of Non-24 in the sighted.
- (January 2014). FDA approves Hetlioz: first treatment for non-24 hour sleep-wake disorder in blind individuals. U.S. Food and Drug Administration. Retrieved June 28, 2014 from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm384092.htm?utm_source=rss&utm_medium=rss&utm_campaign=fda-approves-hetlioz-first-treatment-for-non-24-hour-sleep-wake-disorder-in-blind-individuals
- (2013). Non-24 in Sighted vs. Blind People. National Sleep Foundation. Retrieved June 29, 2014, from http://sleepfoundation.org/non-24/blind.html
- Fadden, James S.P. MA, Vice-President, Sharkey, Katherine MD, PhD, NORD. (March 2013). NON-24-HOUR SLEEP-WAKE DISORDER. National Organization for Rare Disorders (NORD). Retrieved June 28, 2014, from https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1275/viewFullReport
Adrienne is a freelance writer and author who has written extensively on all things health and fitness for more than a decade. You can connect with Adrienne on Facebook here.
Healthline.com is funded, apparently exclusively, by advertising and they own, are owned by or are affiliated with Healthline Networks, Inc., Healthline Corp and YourDoctor.com
Their goal is to educate and empower users with relevant and responsible information in order to foster better communication between doctors and patients.
You can go to http://www.healthline.com for more information on sleep disorders and other related conditions.
69. Next post: –another guest post–
Tags: Circadian rhythm, DSPS, Non-24, Sleep research, Suprachiasmatic nuclei
The online N24 community has decided to name November 24 as N24 Awareness Day. We are encouraging bloggers and tweeters and anyone else with a platform to help spread awareness and knowledge of Non-24-Hour Sleep-Wake Disorder (N24).
The web page which links to these efforts is here (click on the N24 Day Logo):
One important advance was a paper by Kitamura et al. which measured the intrinsic circadian period in 6 patients with N24. They compared it with two groups of individuals without a circadian disorder. One group had an intermediate circadian preference. The other group had an evening preference. The latter group however did not have DSPS, only a preference for being active later in the day.
Kitmura et al. found that the intrinsic period of the N24s was 24.5 hours, which was significantly longer than that of the intermediate types, but not significantly longer than that of the evening types. The average period of the N24s was longer than that of the evening types but because of the great degree of overlap between those groups the difference was not significant. The longest period found in an evening type subject was nearly identical to the longest period among the N24 subjects (around 24.7 hours).
These results suggest that a longer-than-average intrinsic period is a component of N24, but it is not the only causative factor. Other factors, such as differences in phase angle between sleep and temperature rhythms, as found in several studies, may play a role.
Another paper, by An et al. did not discuss N24 explicitly, but the results may have import for those with the condition. They studied the effect of Vasoactive Intestinal Peptide (VIP) on shifting of circadian rhythms in mice and in cell cultures from the SCN. They found that VIP depending on time and dose could either enhance or reduce the mutual synchronization of SCN cells. Further, when SCN cells were less tightly synchronized together, they adapted more quickly to phase changes. This suggests that by manipulation of VIP levels it may be possible to increase the adaptability of the SCN to phase changes. Since N24s with a longer period need to change phase every day if they are trying to maintain a normal schedule, this approach might be of help. It might also help people with DSPS when trying to shift to an earlier sleep phase.
–posted by LivingwithN24
Kitamura S, Hida A, Enomoto M, Watanabe M, Katayose Y, Nozaki K, Aritake S, Higuchi S, Moriguchi Y, Kamei Y, Mishima K. Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type.Biol Psychiatry. 2013 Jan 1;73(1):63-9.
An S, Harang R, Meeker K, Granados-Fuentes D, Tsai CA, Mazuski C, Kim J, Doyle FJ 3rd, Petzold LR, Herzog ED. A neuropeptide speeds circadian entrainment by reducing intercellular synchrony. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4355-61.