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.
Tags: Adolescent, Depression, Diagnosis, Non-24, Sleep disorder, Treatment
I’ve been reading an interesting article on a case of psychiatric misdiagnosis of N24 in a 14-year old. This poor kid was given a long list of severe and pejorative psychiatric diagnoses, all of which resolved completely when his circadian rhythms were normalized with melatonin treatment. He had dropped out of school for two years and was sent to a child psychiatric hospital. After treatment was able to return to school and do well. This case shows how easily N24 (and DSPS) can be misdiagnosed. The boy was also lucky he responded to melatonin as many N24s do not.
Here is the description of his case before proper diagnosis and treatment:
During the 4 years before referral,
the patient suffered from major functioning difficulties
including conflicts with teachers, parents, and peers. He
was described by a licensed child psychologist as being
extremely introverted with severe narcissistic traits, poverty
of thought, and disturbed thinking, including
thoughts with persecutory content and self-destruction
that led to a paralyzing anxiety, anhedonia, social isolation,
and withdrawal. Assessment of learning disabilities
revealed difficulties with written language and poor
visual and auditory memory. Assessment also revealed
above-average performances in verbal comprehension
and abstract reasoning.
Two years before referral, the patient dropped out of
school and was sent to an inpatient child psychiatry center.
Three months of psychiatric evaluation yielded diagnoses
of atypical depressive disorder with possible
schizotypal personality disorder. He was described as
sleepy and passive, especially in the mornings.
The patient was diagnosed using actigraphy (a wrist monitor that measures movement) and with 24 hour sampling of melatonin and temperature rhythms. This is his actigraphy chart showing the classic N24 pattern in which the waking period shifts later each day. The black peaks on the chart show movement, indicating the time of day or night during which he was awake.
Treatment with 5mg of melatonin (a large dose) at 8pm resulted in a normalization of his circadian rhythms within a month.
Here is how he was described after proper diagnosis and treatment:
The patient returned to school after a 1 years absence
and succeeded in filling the gaps of missing studies. At the
end of the first semester, his school report showed excellent
results. His parents also reported an improvement in
the patients relationship with his family and peers.
In a psychiatric evaluation by licensed psychiatrists,
none of the previously described severe diagnoses were
present, and the boy showed no evidence of psychopathology,
as was previously thought.
One wonders how many adolescents — and adults — are misdiagnosed with various severe psychiatric disorders simply because no one looked for a circadian rhythm sleep disorder. The case was reported by Yaron Dagan and Liat Ayalon two of the best researchers on the clinical manifestations of N24 .
1. Dagan Y, Ayalon L. Case study: psychiatric misdiagnosis of non-24-hours sleep-wake schedule disorder resolved by melatonin. J Am Acad Child Adolesc Psychiatry. 2005 Dec;44(12):1271-5.
–Posted by LivingWithN24
Next post: 63. Sleep research in the USA
Tags: Body clock, Circadian rhythm, Disability, Japanese study, Non-24, Prevalence, Sleep disorder
About 50% of the totally blind have Non-24-hour Sleep-Wake Cycle Disorder while it is very rare among sighted people. People with Non-24 cannot adjust to the environmental 24-hour cycle.
If Hayakawa et al. are to be believed, there have been only 96 cases of N24 in sighted people reported in studies, worldwide, ever. The first 39 were reported in 26 separate studies dated 1970-2003. Hayakawa’s group reported on 57 cases in a report in 2005*. These 57 were diagnosed in Japan in 1991-2001. So what have I learned from that paper?
Are there equally many men and women? No, there are more than two and a half times as many men.
Is Non-24 about as common as the other Circadian Rhythm Disorders (CRDs)? No, the other CRDs together, primarily DSPS, are six times as common.
Do people with Non-24 have anything else in common physically? No. Eye examinations, blood counts, serum biochemistry, electrocardiography, electroencephalography and brain MRIs show nothing special.
Socially? 89% were unmarried and 39% were unemployed.
Had they any health problems in common before the onset of free-running? 28% had psychiatric problems (obsessive-compulsive, adjustment, schizoprenia, anxiety or depression and often associated social withdrawal), not remarkably higher than the general population. But more than a fourth had DSPS before developing Non-24.
How old were they at the onset of Non-24? 86% were ten to twenty-nine years old, none younger than ten. Sex had no effect on the age of onset. (None of the subjects was over 50.)
Do the hours of sleep correlate to the length of the endogenous circadian cycle? Most of the subjects’ cycles were between 24.5 and 25.5 hours, with only one having a cycle longer than 26.5 hours. Subjects slept between less than 7 hours to more than 12, with the majority sleeping 9-11 hours. But there was no correlation between the period of the sleep-wake cycle and sleep length, and neither was affected by sex nor employment status.
How debilitating is the disorder? “98% had a history of disturbed social functioning due to inability to regularly attend school or work.”
Do people with Non-24 often develop psychiatric problems after the onset of the disorder. Yes, but depression only, not the other disorders. “It is possible that these patients had tried to adapt themselves to their social life and failed, leading to psychological stresses that could have precipitated their depression.”
How does Non-24 in sighted people differ from that of people who are blind? The blind generally have a shorter circadian period, and it doesn’t fluctuate over time. In sighted people, the period tends to be longer when sleep onset is in the daytime than when a person falls asleep during nighttime.
*Tatsuro Hayakawa, Makoto Uchiyama, Yuichi Kamei et al. Clinical Analyses of Sighted Patients with Non-24-Hour Sleep-Wake Syndrome: A Study of 57 Consecutively Diagnosed Cases. SLEEP 2005;28(8):945-952
Next post: 62. Psychiatric misdiagnosis of N24
Tags: Circadian rhythm, DSPS, Non-24, Sleep diary, Sleep disorder
Keeping a sleep log or a sleep chart is one of the keys to getting a proper diagnosis of a circadian sleep disorder. Oftentimes someone will describe their sleep patterns, but it’s not always clear from the description when exactly they sleep. For example, someone will say they “keep going to bed later and later.” Depending on what they mean, that could either describe Non-24 Hour Sleep-Wake Cycle Disorder (N24) or a gradually worsening case of Delayed Sleep Phase Syndrome (DSPS). But a quick look at a sleep chart will usually clear up the distinction.
My eponymous co-blogger Delayed2Sleep, who has, of course, DSPS, has posted several of her sleep logs. Today I am going to post some of my sleep charts. My name is LivingwithN24 and I have, you guessed it, N24.
One thing I should note to start is that I have always charted my sleep on a vertical chart, whereas D2S has used a horizontal layout, so you’ll need to rotate the charts to compare them. I have also “double-plotted” some of my sleep charts. That means each line on the chart encompasses 48 hours. That’s a standard method in sleep studies as it helps the patterns to stand out more clearly.
These charts show a textbook case of N24. The phrase “textbook case” is not a metaphor here; the medical journal articles about my case are commonly cited in reviews of circadian sleep disorders. So there is no doubt you are looking at a case of N24 sleep. One can see that the sleep chart of an N24 shows a characteristic diagonal pattern as the bedtime and waking time slides gradually later each day. Unlike the case of DSPS, the delay does not stabilize at a particular clock time. Someone with DSPS may for example end up going to bed always around 6am for an extended period. Someone with N24 who goes to bed at 6am on Monday will likely go to bed at 7am on Tuesday, 8am on Wednesday, 9am on Thursday etc. until they have gone all the way around the clock. The delay is not always by one hour — I just chose that for simplicity. In my case I tended to delay 1.5 hours per day, meaning my “day” was actually 25.5 hours.
One can see in this chart that there is some irregularity in the sleep times, and there may also be daytime naps. Both of these showed up a lot in January and February of that year. But there is a nonetheless a clear pattern to the sleep. In some months such as March, April and May it stands out especially clearly.
It might also be of interest to compare these charts to another type of chart. In circadian medicine a technique called actigraphy is used. The patient wears a device called an actimeter on their wrist which records movement. Since people tend to move about a lot more when awake than when asleep, actigraphy can be a way of confirming the sleep times of a patient with N24 or DSPS. Here is an actigraphic chart of my sleep from around the same time as the sleep logs. The difference is the black squiggles on the actigraphic chart show time awake, rather than asleep, but the same diagonal pattern is present.
Now those charts are from 1991. The readers of this blog are clever folks and have no doubt noticed it is now 2010. I did this for a reason. Most of the studies of N24 have looked the subjects at one point in their lives. Few, if any, have examined how the sleep patterns of N24 change over the course of many years. I have noticed a number of changes in my sleep between 1991 and today.
One thing I noticed is that it is much more difficult to control my N24 with lights, darkness and sleeping medications. In fact, over this summer it became impossible. So in September I stopped using the lightbox and the sleeping pills to see what my sleep would do on my own.
Here is a sleep chart I made for the last 5 weeks (Sept 18-Oct 25, 2010). Instead of making the chart by hand I used the SleepChart program from supermemo.com.
This is quite different from the 1991 charts. While there is still a recognizable diagonal drift of the sleep times, it is much more erratic. The times of sleep are much less regular. Also there is a marked tendency to show two or more periods of sleep instead of one for each circadian day.
In some ways this pattern of sleep is in between that of Non-24 Hour Sleep Wake Cycle Disorder and that of Sleep Wake Cycle Disorder – Irregular Type. In the irregular type of sleep disorder, the person sleeps at almost random times of day or night and for varying lengths of time. Usually there are several short periods of sleep scattered at various time around the clock.
My sleep has not become completely irregular, but it is getting there. This is, to put it mildly, not a good thing. N24, bad as it is, has a least a little predictability to it. I could never predict my sleep out several weeks as some very regular N24s could do. But I could at least predict it fairly well 5 or 6 days out. Now I can barely predict what it will do from one day to the next and the urge to sleep or be awake comes upon me at almost random times.
Usually irregular sleep patterns are associated with conditions involving brain damage (injuries, tumors) or deterioration (dementia). However I suspect that in cases of severe circadian disorder the circadian system may deteriorate over time, leading to an evolution towards an irregular sleep pattern. My co-blogger has remarked that her DSPS sleep has some irregular elements as well.
Instead of a static snapshot of sleep which classifies the disorders as DSPS, N24 or irregular, research needs to look at sleep disorders as dynamic, evolving conditions. If someone has say, heart disease, we understand it will manifest itself differently at age 20 and 40 and 60. The same may be the case with circadian disorders. I had some sleep abnormalities from birth, classic DSPS from age 15 to 27, and N24 from then on. Now I seem to be trending towards irregular sleep. My approach to coping with this condition will have to change as well, but how that will happen I don’t yet know.
–posted by LivingWithN24
Next post: 61. Questions and answers about Non-24
Tags: Body clock, Chronotherapy, Circadian rhythm, DSPS, Non-24, Treatment
Treatments for circadian sleep disorders fall into three general categories. The first combines phototherapy and scototherapy, that is treatment with light and dark. The second is pharmacotherapy, usually using melatonin or one of its drug analogs. The third treatment is what I will discuss today and is known as chronotherapy.
None of these forms of treatment is universally successful — or there would be little need for this blog. Chronotherapy was the first treatment found to be successful for some cases of DSPS and thus was a major advance in treatment . The researchers who discovered it should be commended. But many valuable medical treatments also carry inherent risks. In particular anyone planning chronotherapy needs to know that it poses a risk of converting DSPS into the even more severe disorder known as non-24 hour sleep wake cycle disorder (N24).
This risk was first reported in a letter to the New England Journal of Medicine in 1992 by Dan Oren and Thomas Wehr of the NIH . They described three patients who had long-standing DSPS and had attempted to treat it by means of chronotherapy. In each of those cases the result was a persisting case of N24.
I can vouch for the accuracy of the NEJM article for one of the cases described is actually mine. I had DSPS for over 15 years before attempting to treat it by chronotherapy. That was the start of my current condition of N24.
The reason I am posting about this at this time is that I have gotten emails from people in recent years who have tried chronotherapy and who had also ended up as N24. These people were startled to find out that this risk was known 18 years ago. They were not aware of this risk prior to starting chronotherapy. Since chronotherapy is widely recommended, but the risk it poses is not widely known, I thought the subject needed to be addressed.
Two questions arise. Why does chronotherapy cause N24 in some cases; and how often does it do so?
To address the “why” question, let’s first review the difference between DSPS and N24. Someone with DSPS is unable to sleep except at a very delayed hour compared to most people. For example someone who sleeps every day from 4am to noon and cannot advance their sleep to normal hours would have the diagnosis of DSPS.
N24 is somewhat different. The sleeping time of someone with N24 changes from day to day. If they start out falling asleep at 4am, the next day they might not fall asleep until 6am, the following day at 8am, then 10am and so on, until they go around the clock. They might have a 26 hour day, as in that example, or any other day length longer than 24 hours, hence the name non-24 hour sleep-wake cycle disorder.
Returning to DSPS, while someone with DSPS cannot advance their sleep — cannot start going to bed at 2am if they are used to going to bed at 4am — they often can delay their sleep if they try. Thus it was proposed that they could normalize their sleep by going to bed later and later until they rolled around the clock to a normal sleep time. If they started at 4am they would be told to go to sleep the next day at 7am, then 10am then 1pm and so on until they reached a normal bedtime.
Described this way, it’s easy to see that chronotherapy for DSPS consists of temporarily following a schedule like that of someone with N24.
This first phase of chronotherapy is supposed to be followed by a second stabilization phase once the desired sleep time is reached. In the stabilization phase the subject is supposed to rigidly stick to the new bedtime and wake time.
Sometimes this works. Chronotherapy has been successful in some individuals. But not always. The N24 state, once entered into, is not so easy to reverse. In some persons, it is irreversible and they find that chronotherapy, far from curing their circadian problem, has instead converted it to a new, more impairing form.
There are two reasons why the transition to N24 can be difficult to reverse.
The first reason has to do with the relative phase of sleep compared to the phase of the body’s circadian rhythm which determines the phase response curve to light. In many cases of DSPS the delay of the sleep cycle relative to the light PRC means that such “nite owls” are asleep during the time at which the body need to be exposed to light in order to advance the timing of the circadian rhythm. When doing chronotherapy one goes to bed even later relative to the PRC. This decreases light exposure during the phase advance portion of the PRC and increases the light exposure during the phase delay portion of the PRC, causing a progressive delay of the circadian rhythm. The circadian rhythm determines the rhythm of sleep propensity so that delays as well. This sets up a positive feedback effect which tends to perpetuate the N24 state once it has been started. To reverse N24 once this feedback loop is started is very difficult.
A second reason may relate to findings in studies of animals on non-24 hour schedules (produced by a non-24 hour zeitgeber such as lights that go on and off every 25 hours). It has been found that prolonged maintenance on such a schedule changes the apparent period of the circadian rhythm, so that even when released from the non-24 hour zeitgeber into an environment of constant light or dark they continue to show signs of their prior N24 schedule . This was the reason cited in the original NEJM article.
How large is the risk of inducing N24 after chronotherapy? The NEJM article mentions 3 patients, which seems small until one recalls that the original article on chronotherapy in 1981 only cited 5 successful cases . There have been other reports of successful chronotherapy since then, but usually with small numbers of patients. Published cases of chronotherapy leading to N24 have been fewer; but as I mentioned, I have heard personally from other people in whom this has happened. There has been no systematic attempt to determine the relative risk. But given the small numbers of reported chronotherapy successes, the even smaller numbers of conversion to N24 cannot be considered negligible.
It may be that this risk could be reduced by the additional use of light boxes and dark therapy during the stabilization phase of chronotherapy. But this is speculation. The authors of the NEJM article suggest a slow advance of DSPS using light therapy as preferable to chronotherapy.
Of course not all DSPS patients will respond to slow phase advance by light therapy. For those who don’t the possibility of chronotherapy is tempting.
I am not someone who likes to make blanket statements. I would not suggest that chronotherapy be abandoned entirely. It does work for some. Nor am I criticizing the researchers who invented chronotherapy. Since prior to that there were no treatments at all for DSPS it was an important advance, and one that may still have its uses. But what I would say is that anyone starting chronotherapy needs to know that there is a risk it could make their circadian disorder worse. It is a calculated risk, although one in which we have little data to make that calculation accurately.
Many web sites and even medical texts mention the use of chronotherapy. Very few mention the risk that it can induce N24. One would have thought that an article in the prestigious New England Journal of Medicine would have been enough to get the word out, but clearly this aspect needs to be more widely discussed, which is why I am posting this.
—Posted by LivingWithN24 aka “L“
1. Czeisler CA, Richardson GS, Coleman RM, Zimmerman JC, Moore-Ede MC, Dement WC, Weitzman ED. Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep. 1981;4(1):1-21.
2. Oren DA, Wehr TA. Hypernyctohemeral syndrome after chronotherapy for delayed sleep phase syndrome. N Engl J Med. 1992 Dec 10;327(24):1762.
3.Pittendrigh CS, Daan S. A functional analysis of circadian pacemakers in nocturnal rodents. 1. The stability and lability of spontaneous frequency. J Comp Physiol [AI 1976;106:223-52.