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Circadian rhythm sleep disorders (crsd)

Sleep Medicine Reviews, Vol. 6, No. 1, pp 45–55, 2002 doi:10.1053/smrv.2001.0190, available online at on MEDICINE
Yaron Dagan
Institute for Fatigue and Sleep Medicine, “Sheba” Medical Center, Affiliated to “Sackler” Medical School,Tel Aviv University, Israel KEYWORDS
Circadian Rhythm Sleep Disorders (CRSD) are a group of sleep disorders characterized by a malsynchronization between a person’s biological clock and the environmental 24-h schedule. These disorders can lead to harmful psychological and functional difficulties and are often misdiagnosed and incorrectly treated due to the fact that doctors are unaware of their existence. In the following review we describethe characteristics of CRSD, their diagnosis, treatment as well as their relationship to psychopathology, psychotropic drugs and head trauma.
 2002 Published by Elsevier Science Ltd INTRODUCTION
The inborn human sleep-wake schedule is longer Twenty years ago Weitzman et al. [5] first described than 24 h. It is synchronized to the external 24-h 30 of their insomnia patients (7%) as suffering from day, and reacts to environmental zeitgebers (time Delayed Sleep Phase Syndrome (DSPS). These cues). The environmental zeitgeber – bright light – patients had a tendency to fall asleep very late at seems to play the crucial role in this process [1, 2].
night and to experience difficulty rising at a desired The sleep-wake schedule is synchronized also with time in the morning. They also found that when other circadian cycles in the body: body tem- these patients were allowed to sleep without ex- perature, and the secretion of: melatonin, growth ternal restrictions, they slept for a normal lengthof time and exhibited no pathology in their sleep architecture. Their patients were younger than Human beings sleep at night and are awake during other types of insomniacs, without differences of the day. This essential phenomenon so taken for sex prevalence, displaying no specific psychiatric granted can become chronically impaired in some disorders, and of various ages of onset. This dis- people leading to a group of disorders called: Cir- covery led to the recognition of the existence of cadian Rhythm Sleep Disorders (CRSD) [3, 4].
Circadian Rhythm Sleep Disorders (CRSD) other These disorders are usually unfamiliar to the phys- ician thus frequently misdiagnosed and incorrectly Today, the criteria for the definition and diagnosis treated. The aim of this review is to shed light on of CRSD (formerly Sleep Wake Schedule Disorders these disorders: characteristics, diagnosis, treat- – SWSD ) are described by the International Classification of Sleep Disorders (ICSD) [3, 4].
According to this definition, CRSD constitute amisalignment between the patient’s sleep patternand that, which is desired or regarded as the societalnorm. Sleep episodes occur at inappropriate times Correspondence should be addressed to: Y. Dagan, Institutefor Fatigue and Sleep Medicine, “Sheba” Medical Center, Fax: and as a result, wake periods occur at undesired 972-3-5349368. E-mail: times, therefore, the patient complains of insomnia 1087–0792/02/$-See front matter  2002 Published by Elsevier Science Ltd or excessive daytime sleepiness. For most of the Figures 1–3 display the rest-activity patterns of CRSD, the major sleep episode is of normal duration three patients suffering from Delayed Sleep Phase with normal REM/NREM cycling, although in- Syndrome, Non-24-h Sleep–Wake Syndrome and termittent sleep episodes may occur in some dis- Irregular Sleep–Wake Pattern, respectively. The black areas represent activity, while the white ones 1. Delayed Sleep Phase Syndrome (DSPS): in this disorder the major sleep episode is delayed in CRSD CHARACTERISTICS
relation to the desired clock time resulting insymptoms of sleep-onset insomnia or difficulty The pioneer report by Weizman et al. [5], published in awakening at the desired time (Fig. 1).
in 1981, was followed by only a few studies, based 2. Advanced Sleep Phase Syndrome (ASPS): the on small numbers of patients with no more than major sleep episode is advanced in relation to 30 participants [6]. The only large study on CRSD the desired clock time, resulting in symptoms of patients [7] includes a survey of the characteristics compelling evening sleepiness, early sleep onset, of 322 patients suffering from CRSD and a case- and an awakening that is earlier than desired.
control study comparing a group of 50 CRSD 3. Non-24-h Sleep–Wake Syndrome (Free-Running patients and 56 age and sex matched normal sub- pattern): consists of a chronic steady pattern jects. The major findings were: a great majority comprised of several hours daily delays in sleep (84.6%) of the patients were found to have DSPS, onset and wake times in an individual living in 12.3% had a Non-24-h Sleep Wake Syndrome, while only a handful of patients were diagnosed with 4. Irregular Sleep–Wake Pattern (disorganized): an Irregular Sleep–Wake Pattern (1.9%) and ASPS consists of temporally disorganized and variable (1.3%). In a report from a sleep clinic in Japan similar episodes of sleep and waking behaviour (Fig. 3).
data was recorded [8]. The low prevalence of ASPS 5. Shift work and 6. jet lag that are beyond the in CRSD may be due to fact that ASPS is a condition that is better tolerated than DSPS. It is much easier to keep oneself awake for a few hours after the be 0.13% in Japan [9] 0.17% in Norway [10] and habitual bed-time, than to force oneself to fall asleep 7.3% of adolescents in the western population [11].
a few hours before one’s habitual bed-time – a veryfrustrating if not an impossible task.
The majority of patients (89.6%) reported onset BIOLOGICAL ASPECTS OF CRSD
of CRSD in early childhood or adolescence; no sexdifferences were evident; a familial trait existed in CRSD patients differ from night or morning type people (“owls” and “larks”) in the rigidity of their The reported prevalence of CRSD in these stud- maladjusted biological clock. While “owls” and ies [7, 8] reflects the population of patients who “larks” prefer morning or evening, they are flexible approach sleep specialists for help. There is, at the and can adjust to the demands of the environmental present time, very limited data available regarding clock. CRSD patients, on the other hand, appear the prevalence of CRSD in the general population.
to be unable to change their clock by means of The prevalence of the disorder was estimated to Irregular (or Diosorganized) Sleep Wake Pattern.
In CRSD not only the sleep–wake cycles deviates authors explain the patho-physiology of DSPS and but also other circadian physiological rhythms such the rigidity of their internal clock by these findings.
as: melatonin and body temperature [12–14]. The Another study [14] compared the core body involvement of several biological rhythms in this temperature schedule of DSPS compared to normal disorder may be a part of the explanation why is controls. They found that sleep length and tem- it so difficult for these patients to change their perature nadir to sleep offset interval were sig- sleep–wake schedule. Uchiyama et al. [15] looked nificantly longer in DSPS than in the control group.
for the cause for the inability of CRSD patients to They suggest, that the rigidity of DSPS patients’ reset sleep phase. They studied 11 DSPS patients sleep–wake schedule is a result of their inability to and 15 normal control in an ultra short sleep–wake phase advance their temperature circadian clock, in schedule measuring melatonin secretion in dim light the same way that daily body temperature was condition. DSPS patients failed to compensate for identified as a physiological component in ad- previous sleep loss compared to control subjects.
justment to shift work and jetlag [16].
Phase angle between sleep propensity rhythms and Is the hereditary trend reported clinically re- melatonin was wider in DSPS than in controls. The flected in genetic studies also? A study investigated the human leukocyte antigen (HLA) types A, B, and Administration of B12 has been reported to DR, of 42 DSPS patients and compared its frequency normalize human sleep–wake rhythm disorders with those of 117 healthy control subjects [17].
such as Non-24-h Sleep–Wake Syndrome, DSPS, or Only HLA DR1 was significantly higher in DSPS, insomnia. However, the mechanisms of the action which indicates possible association between this of B12 on the rhythm disorders are unknown [28].
antigen and DSPS and maybe the genetic factor for It may act by changing the ocular receptors’ affinity predisposition to DSPS. Others [18, 19] suggest to light, or exert a direct influence on melatonin that several mutations in the human melatonin 1a [29], yet there is little experience with this treat- [hMella] receptor gene are the cause of the bio- ment and very few accounts appear in the literature.
All the reports of vitamin B12 efficiency for CRSDwere based on open studies, thus the effect ofvitamin B12 has not been accurately evaluated.
There is only one double-blind study [30] evaluatingthe effect of 3 mg/day methylcobalamin or placebo The best method to make the diagnosis of CRSD administered for 4 weeks to DSPS patients. No is by a clinical interview and a week of actigraphic significant differences were observed between the monitoring or sleep log in free conditions. Moni- two groups in sleep–wake cycles and in the feeling toring the sleep–wake schedule under forced con- ditions can mask the pattern of the schedule thus Light therapy, which became increasingly popular misleading the diagnosis. The actigraph is a watch as the importance of light in resetting the circadian size device worn on the wrist sampling hand motion.
system was recognized, involves using morning A computerized algorithm can provide highly re- bright light exposure to induce a phase advance in liable data on sleep and wake periods of the patient both sleep onset and wake times [31]. Even very [20, 21]. We believe that actigraphy is the best short term (5 days) of phototherapy on six patients objective diagnostic tool for CRSD, as opposed to with DSPS proved advancement of sleep phase and polysomnography (PSG), which is not an adequate body minimum temperature [32]. Practice para- tool for the assessment of CRSD. This is due to meters for the use of light therapy in the treatment the nature of CRSD, which requires monitoring for of sleep disorders was published by the Standards several days in order for the patients’ sleep–wake of Practice Committee, American Academy of Sleep pattern to manifest itself clearly. This is very difficult Medicine [33]. They maintain that, light therapy has to do with PSG, yet can be perfectly demonstrated been found to be a useful treatment for DSPS and by actigraphy (see Figs 1–3). Melatonin secretion ASPS, but its benefits for the treatment of non-24- and/or temperature measure for at least 36 hours h sleep-wake syndrome, jet lag and shift work every two hours can be an additional diagnostic are less clear. However this treatment demands 30–60 min of sitting in front of a light-box everymorning or evening, which is complicated to managefor many DSPS patients.
While chronotherapy and light therapy are de- manding and difficult treatments, which usually lead Patients suffering from DSPS are treated with one to compliance problems (thus giving rise to few of, or a combination of several methods, such aschronotherapy [22], light therapy [23], vitamin B12 reports in the literature), melatonin administration, [24], or melatonin administration [25, 26].
is a relatively simple and easy treatment option.
The term chronotherapy in sleep medicine refers Studies have shown that melatonin has a sleep- to a behavioral technique in which bedtime is sys- promoting and entraining action when taken in the tematically delayed, so following the natural tend- evening. The effects of the administration of small ency of human biology. This is done, until sleep doses of melatonin (0.5–5.0 mg.) have been shown onset time coincides with the desired sleep time, to follow a phase-response curve that is nearly the where the conventional 24-h day is re-established.
opposite of light curve [34]. Phase advances are Consequently, the patient is advised to maintain the produced by melatonin administered in the evening, newly achieved bedtime rigidly, and from then on while phase delays appear when it is administered in the early morning [35]. It is also been shown that melatonin induces temperature suppression Dahlitz et al. [25] illustrated that an oral dose of [36], and that there is a direct relationship between 5 mg of melatonin taken in the evening causes a the ability of melatonin to phase shift the endo- significant phase advance toward conventional times genous circadian clock and its temperature sup- of both sleep onset and awakening with no significant pressing quality [37]. These characteristics seem to changes in sleep duration or architecture. Oldani be what makes melatonin an effective means of et al. [51], treated six DSPS patients with 5 mg of dealing with chronobiological disorders. In studies, melatonin for a period of one month, with similarly where only part of them were randomized placebo- positive results, and no changes to sleep ar- controlled, melatonin proved to be effective in: shift chitecture or duration. In both studies, however, work induced sleep disorders [38], sleep dis- the pretreatment sleep pattern returned 2–3 days turbances caused by a de-synchronization of the endogenous sleep-wake cycle from lighting cues in While the above studies all support the efficiency blind, geriatric and brain damaged subjects [39] of melatonin treatment for DSPS, they were all CRSD, including DSPS [25, 26, 40]. In a double- carried out on a relatively small number of DSPS blind placebo-controlled cross-over study [41] the patients. Over the past six years, over 400 people effect of 5 mg melatonin administration to 25 DSPS suffering from DSPS have been referred to our patients was investigated. The influence of melatonin sleep and chronobiology clinic. Most of these was assessed by: 24-h melatonin and rectal tem- patients were treated with melatonin based on perature curve, polysomnography, actigraphy, sleep the principles suggested by Dahlitz et al. [25], and log and subjective sleep quality assessment. After received guidelines regarding maintenance of their treatment there was a significant advancement in new sleep patterns. After a substantial period of melatonin curve (approximately 1.5 h), actigraphic time had elapsed, we decided to conduct a subjective and PSG sleep onset and offset and people felt follow-up study [26]. In this study, we attempted more refreshed in the morning. The temperature to investigate the effectiveness of the treatment curve did not move significantly. Another study and the existence of any possible side effects. We comparing melatonin and placebo treatment for also hoped to ascertain whether a relationship exists DSPS confirmed these results [42]. Recently several between the length of effectiveness of the treatment studies reported on the effects of melatonin on the and certain aspects of the illness. This study, which quality of life of DSPS patients [43], for DSPS accompanied routine treatment in our sleep clinic, patients suffering from chronic headache [44] and examined the efficiency of melatonin treatment in for the regulation of CRSD of mentally retarded a relatively large sample of DSPS subjects by means children [45, 46]. There are controversies about its of subjective reports. A sample of 61 subjects, 37 males, and 24 females were diagnosed with DSPS It has been shown that melatonin has an ex- by means of clinical assessment and actigraphy. Their tremely wide margin of safety, at least in terms of mean pre-treatment falling asleep and waking times short-term side effects. In a study that examined the effects of oral melatonin on skin color and the 98.58 min), respectively. They were treated with a release of pituitary hormones, five patients with six-week course of treatment comprising 5 mg of hyper-pigmented skin were given 1 g/day of me- oral melatonin taken daily at 22.00 h. Twelve to latonin orally for a period of 30 days, with minimal eighteen months after the end of the treatment, a adverse effects. These patients did complain of survey questionnaire was sent to the home of each increased drowsiness, but a thorough examination subject to investigate the efficiency of the melatonin did not reveal any evidence of toxicity [49] despite treatment and its possible side effects. 96.7% of the the very high dosage used in this study (200–2000 patients reported that the melatonin treatment was times greater than that generally used for the treat-ment of circadian disorders). It should be noted helpful, with almost no side effects. Of these, 91.5% that even a 0.5–5.0 mg dosage of melatonin is higher reported a relapse to their pre-treatment sleeping than normal nocturnal levels of melatonin in the patterns within one year of the end of treatment.
blood. Moreover, Arendt points out that no data Only 28.8% reported that the relapse occurred exist on long-term studies in humans [50], therefore within one week. The pre-treatment falling asleep questions of safety have yet to be fully researched and waking times of patients in whom the changes were retained for a relatively long period of time were significantly earlier than those of patients CRSD patients, to which he or she has been sub- whose relapse was immediate (t=2.18, P<0.05; t= jected since early childhood or adolescence, adds 2.39, P<0.05, respectively), with no difference in psychological distress to the practical difficulties of sleep duration. There are CRSD patients for whom coping with life. Several studies found depression all these treatment modalities fail to help. In these to be frequent in DSPS [6, 56, 57] Is it an outcome cases it becomes a CRSD Disability [53] and the of their failure to adjust to the environmental every- only successful treatment is rehabilitation i.e. for day life demands or simply symptoms of fatigue as the patient to adopt a new career that enables a result of ongoing partial sleep deprivation? to work within the limits of his chronobiological Attention Deficit Hyperactive Disorder (ADHD) has also been found to be related to the instabilityof the sleep-wake system [58]. Thirty-eight school-age boys with ADHD and 64 controls were ex-amined with actigraphs and sleep diaries over five CRSD IN PSYCHIATRY
consecutive nights. Discriminant analysis revealedthat children’s classification (ADHD versus control) It has been found that there is a high prevalence of could be significantly predicted on the basis of their learning disorders (19.3%) and personality disorders (22.4%) in people who have CRSD [7]. The high prevalence of personality disorders in CRSD characteristic of numerous psychopathologies such patients has been confirmed in a controlled study, as depression, anxiety, PTSD etc. We wish to em- which found that individuals suffering from CRSD phasize the fact that no existing psychopathology is are characterized to a greater extent by personality characterized by a sleep disorder of the circadian disorders than a control group [54]. In a com- plementary study [55] 63 hospitalized adolescentswere studied. None of them had any diagnosedmedical disorders, and all were being treated with DRUG-INDUCED CRSD
psychiatric drugs. Ten subjects were diagnosed assuffering from DSPS according to a sleep–wake Can pharmacological treatments cause CRSD as a schedule structured interview. Subjects diagnosed side effect? Wirz-Justice et al. [59], describe a case as suffering from personality disorders had a sig- of a patient with chronic schizophrenia, treated with nificantly higher probability of also suffering from haloperidol, and showing signs of CRSD. Changing DSPS. Additional findings were that patients with medication to clozapine showed a direct effect DSPS were more likely to have received an DSM on his sleep and established a more organized IV axis II diagnosis only, and were more likely to sleep–wake pattern. Another report [60] is of a 22 be diagnosed as suffering from a distinct group of year-old male patient who was diagnosed at the age disorders characterized by affective lability. The of 16 as suffering from Tourette Syndrome and findings of DSPS and personality disorders, may severe OCD. The Tourette Syndrome has been lend some support to the hypothesis that inborn successfully treated with haloperidol for 6 years.
peculiarities in the sleep–wake rhythm lead to the After 2 years of treatment with haloperidol he social and functional difficulties characteristic of began showing signs of disorganized sleep, which clearly were not present before. The patient com- Learning disorders and even personality disorders plained of difficulties in falling asleep at a regular are related or may even be an outcome of CRSD.
time and a severe problem in awakening at the A child who does not get enough sleep at night will desired time for daily activity. The problem has not be alert during the day in school, and is prone caused him severe difficulties in day-to-day func- to have trouble keeping up with the other children.
tioning and due to this he was unable to keep a job Frequently, the patients’ parents, teachers, doctors, on a regular basis. He was a very talented computer or psychologists believe that the patients’ biological systems analyst and had started to work from home sleep–wake problem and the accompanying dys- function at school are motivational or psychological A night of polysomnography revealed no sleep in nature, a belief that during the years, the patients apnea. Three weeks of actigraphy done in a free tend to adapt themselves. This attitude toward running condition showed a disorganized sleep– wake schedule. The patient was taken off the hal- minor [62]. This group is usually characterized as operidol and was given risperidone 1 mg/day. He suffering from Disorganized Circadian Rhythm Sleep reported an improvement in his sleep difficulties Disorder [DCRSD] with onset later than is common and no worsening of his Tourette symptoms. A for other types of CRSD. This is opposed to the revised actigraphic monitoring confirmed the findings of Quinto et al. [63], who described one patient’s subjective feeling. Additional 5 mg oral case of DSPS and not DCRSD occurring after brain melatonin taken at 21.00 h was added to the trauma and the findings of Negtegaal et al. [64]. In risperidone and a full recovery was documented in all the cases there were no objective pathological a third follow-up actigraphy. This was accompanied finds in imaging (CT, MRI or EEG), and no cognitive by his feeling of a significant improvement. The dysfunction, but patients complained of difficulty in patient was unable to find enough superlatives to falling asleep and waking up as well as sleepiness describe the change in his life. After years of dif- during the day. All of the patients had no complaints ficulties in coping with his occupational and social of sleep–wake cycle inconsistency previous to the life due to unconventional sleep timing, he at last trauma, but all of them had been misdiagnosed for started to have an organized schedule that has years following their injury. The diagnoses were enabled him to recover his diurnal life.
often psychiatric in nature, and often mistreated Is haloperidol the only psychiatric drug that can pharmacologically. Some cases were given the psy- provoke CRSD? Hermesh et al. [61] reported on chological diagnosis of PTSD (Post-Traumatic Stress ten patients who developed typical DSPS during Disorder) although they did not meet the criteria treatment with the specific SRI agent fluvoxamine for PTSD. Many patients were just thought to be (FVA), prescribed for their obsessive-compulsive malingering in order to gain financially from their disorder. The delay in falling asleep ranged between 2.5–4 h later than the patients’ normal sleep routine.
While treatment with melatonin is useful in DSPS, In the first five patients, DSPS was initially mis- it has been found to be little or no help in treating diagnosed as FVA induced somnolence or sedation.
DCRSD following head trauma [62]. Since there is The causal role of FVA in the development of DSPS no effective pharmacological therapy, the approach in this series is corroborated by several pieces of to CRSD after head trauma should be rehabilitation clinical evidence: FVA was the only drug taken by [53]. As with any other disability following physical these patients. In all patients, first appearance of trauma, the patient must understand and accept DSPS had occurred following FVA initiation. In all that the disability is permanent and should be guided 10 cases, where FVA was withdrawn, or the dose in overcoming it. The patient should be encouraged considerably decreased, DSPS disappeared. Re-ex- to consider changes in his daily lifestyle, possibly a posure of 3 patients to FVA again led to the return change of occupation that conforms more to the of DSPS. No case of spontaneous remission of DSPS hours he is awake, possibly, in certain cases, working was observed, even when FVA was administered from home, and setting his own timetable.
for longer than 2 years (range 5.5 weeks–2.2 years).
It is not yet clear why minor head trauma causes Emergence of FVA-induced DSPS was not im- the onset of CRSD. Possibly there is a micro damage mediate, and at least 5 days of ingestion, with no to the pathways that are responsible for the syn- less than 100 mg/d of FVA, had passed before chronization between internal and external clocks.
patients first notice the change in their normal sleep It is also possible that this damage is the reason pattern. The authors conclude that FVA can cause why we are unable to treat DCRSD brought on by DSPS, which is often overlooked by the clinician head trauma successfully with melatonin.
or misdiagnosed as psycho-physiological insomnia.
Additional treatment with melatonin 5 mg at 21.00 h CONCLUSION
can re-organize the sleep–wake schedule of thesepatients thus enable to continue the FVA use.
CRSD are sleep pathologies rarely familiar to doc-tors. Many of our CRSD patients had, for years, been CRSD AND HEAD TRAUMA
wrongly diagnosed by neurologists, pediatricians andespecially by psychiatrists as psycho-physiological It has been found that certain people have developed insomniacs, and therefore unsuccessfully treated, CRSD after head trauma, even when the trauma is usually with sleeping pills [7]. Early onset of CRSD, the ease of diagnosis, the high frequency of mis- Research Agenda
diagnosis and erroneous treatment, the potentially 1. The prevalence of CRSD in the general popu- lation is yet unknown and requires a study.
sequences, and the availability of promising treat- 2. More has to be done in order to understand ments, all indicate the importance of greater the biological mechanisms involved in the de- awareness of these disorders. Doctors from various synchronization of CRSD patients biological chiatrists, neurologists, as well as psychologists and 3. The hereditary trend of CRSD should point teachers should be more alert to the existence of to studies on the genetic basis of the disorder.
4. Are there more drugs for which CRSD is one 5. More research needs to be done on the safety and efficacy of CRSD treatments, including Practice Points
When patients complain of sleep difficulties thedoctor should ask some additional clinical ques-tions about their sleep–wake habits.
If CRSD is suspected, we suggest asking some The author is grateful to Mrs Judith Abadi for her 1. Hunger times: the patient should be ques- tioned about his/her preferable eating hours– whether she/he eats or is hungry during the REFERENCES
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