Sleep
10(2): 101-110, Raven Press, New York
© 1987, Association of Professional Sleep Societies
Four Congenitally Blind Children With
Circadian Sleep-Wake Rhythm Disorder
M, Okawa, T. Nanami, S. Wada, T. Shimizu, Y. Hishikawa, *H. Sasaki,
tHo Nagamine, and :j:K. Takahashi
Akita University School of Medicine, Akita; *Metropolitan Medical Center of the Severely
Handicapped, Tokyo; tNational Institute for Special Education, Yokosuka; and :f:Shiga
University of Medical Science, Ohtsu, Japan
Summary; Four congenitally blind children aged 4-12 years, with severe or
moderate mental retardation, were chronobiologically studied. Three of them
showed a free-running rhythm of sleep-wake, and the fourth showed an irregular sleep-wake rhythm. To entrain their sleep-wake rhythm to a 24-h rhythm,
several trials based on chronotherapy were performed. The free-running
rhythms in the three children were considered their own endogenous rhythms,
revealed through some disorder in the mechanism synchronizing the endogenous rhythm to the normal 24-h environmental rhythm. The irregular sleepwake rhythm in the fourth child may have been the result of immaturity or
failure of the pacemaker of the circadian rhythm. Because of their severe
mental retardation, all the children were lacking in social time cues, which are
the most potent "Zeitgebers" for human biological clocks. Key Words: Blind
children-Circadian rhythm-Sleep-wake-Free-running rhythm.
The light and dark cycle has been shown to be one of the dominant synchronizers of
the human circardian system (1). In blind subjects whose light perception was impaired
to various degrees, a high incidence of sleep-wake disorders was reported (2,3). There
are very few reports, however, on blind children with mental retardation (MR) who
have sleep-wake disorders.
Four congenitally blind children with severe or moderate MR showed a persistent
free-running rhythm or a highly irregular sleep-wake rhythm in an ordinary environment. They were chronobiologically studied in our hospital and several trials based on
chronotherapy were performed in an attempt to entrain their sleep-wake rhythm to the
24-h rhythm.
CASE REPORT
The clinical features of the four patients are summarized in Table 1.
Accepted for publication September 1986.
Address correspondence and reprint requests to Dr. M. Okawa at Department of Neuropsychiatry, Akita
University School of Medicine, Hondo 1-1-1, Akita-shi, Akita, Japan.
101
M. OKAWA ET AL.
102
TABLE 1. Clinical features of four cases
Age
Sex
11
F
2
12
F
3
7
F
4
4
F
Case
Ophthalmological
findings
Bilateral congenital
microphthalmia and cataract
Congenital microphthalmia (left
side), anophthalmia (right side)
Bilateral optic nerve atrophy
Congenital microphthalmia (right
side), anophthalmia (left side)
Light
perceptiona
±
Clinical symptoms
Moderate MR, epileptic seizures,
episodic apnea
Congenital malformations,
severe MR, epileptic seizures
Spastic tetraplegia, severe MR,
microcephalus
Moderate MR
MR, mental retardation.
lacking ( - ); only light and dark perception (±).
a
Case 1
A 1O-year-old girl was born at term by normal delivery. Her weight at birth was 4,270
g. She had congenital blindness due to microphthalmia and cataracts in both eyes. She
started walking at 14 months of age. At 15 months of age, she began to have epileptic
convulsions. At about the same time, her mother noticed that the child went to sleep an
hour later each day. She would lie awake at night and sleep during the daytime for a
period of several days in the course of a month. She had no seizures after the age of 2.5
years.
At 6 years of age, she attended a pre-school for blind children. During this period,
her mother recorded the child's exact sleep-wake pattern each day and noticed that she
fell asleep and awoke ~ 1 hour later each day, which showed an approximate 25-h
free-running rhythm of sleep-wake (Fig. lA). The child could not attend school during
the period of daytime sleeping. To correct her disordered sleep-wake rhythm, her
mother and school teachers tried to interfere with her sleep-wake cycle by means of
forced awakening, but the trial was unsuccessful.
At 8 years of age, her grand mal seizures reappeared. In addition, she began to have
brief apneic episodes accompanied by cyanosis every 2-3 min during the waking state.
She never developed apneic episodes during sleep, however. She began taking 90 mg
phenobarbital and 600 mg sodium valproate. Epileptic seizures disappeared 1 week
after medication was started, but apneic episodes still occurred.
At 10 years of age, she was admitted to Akita University Hospital. She was 145 cm
tall and weighed 64 kg. She had no major deficit in motor functions. Her development
was estimated to be between 1 and 2 years of age.
To entrain her to the usual 24-h rhythm of sleep-wake, phototherapy (illumination of
2,000 Lux at 0600 for 1 h in the room), restricted feeding, and forced awakening were
tried, but these were ineffective (Fig. lB). For her frequent apneic episodes with cyanosis, acetazolamide at a dose of 500 mg/day was very effective. Both phenobarbital
and sodium valproate were gradually decreased to 0 mg.
In April 1985, she entered a junior high school for blind children. Her free-running
rhythm of sleep-wake has persisted, however.
Blood examinations, including blood urea nitrogen, creatinine, total protein, albumin/globulin ratio, sodium, potassium, chloride, and protein-bound iodine, showed
normal results. Chromosomal analysis revealed a normal karyotype with an XX sex
Sleep. Vol. 10, No.2, 1987
FREE-RUNNING RHYTHMS IN BLIND CHILDREN
TIME
0
'82
OF
12
6
103
DAY
18
"
---i
0
-
-,
15
PHOTOTHERAPY
0
--
20
" MEAL
~
SEP
"
OCT -
~
"
25
"
0
~~
'?430
1/1
~ o~ ::~-)
10
NOV
~==-==-==:
===:
o
12
12
o
20
_0__
25
-
=" - -o
TIME OF DAY
:= :
-==-: ~ :
--=..:....-:- -: ---
15
o
ill::-=
~
RESTRICTION
OF MEALTIME
I
FORCED·
~ I A~AI(ENING
I
: La
0
o
,
A
B
FIG. 1. Double-plotted sleep-wake rhythm and therapeutic effects in a lO-year-old blind girl. A: Sleep-wake
rhythm for 2 months, based on the mother's observation. Solid bars represent sleep. Onset of sleep was
delayed by -I hour each day. Cycle of sleep-wake rhythm (t) was 24.S h. B: Effects of trials for entraining
the free-running rhythm to a 24-h rhythm by phototherapy, restricted mealtime, and forced awakening. Phototherapy was not effective. Restriction of mealtime 7 -S h for breakfast, 11-12 h for lunch, and 17 -IS h for
dinner, accompanied by forced awakening during the daytime, had a favorable influence on daily activities,
but the free-running rhythm was unchanged.
,;~
~J
~'
chromosomal complement. Serum levels of growth hormone, ACTH, TSH, HCG, T3,
and T4 examined at 0700 h yielded normal results.
An x-ray film of the scalp revealed a J-shaped sella turcica, but brain CT scan
showed no abnormality. Electroretinogram (ERG) and visual evoked 'potentials were
very abnormal: Independent of the eye, no response was obtained with any of these
tests.
An EEG recorded when she was 10 years of age revealed 8- to 9-Hz IX waves dominant in the bilateral occipital areas during wake time, and spikes appeared in the left
midtemporal and central areas during sleep. Nurses observed her behavior for 55 days
when she was 10.5 years of age, and recorded her daily total sleep time of 10.58 ± 0.71
h (mean ± 1 SD) (Table 2) and with a period of free-running rhythm of sleep-wake
24.8 h. During this observation period, a 24-h polysomnographic recording was made.
Sleep parameters on the 9-h sleep record showed 20.8% of total sleep time to be stage
1; 38.7%, stage 2; 12.9%, stage 3; 17.5%, stage 4; and 10.1%, stage REM. The percentage of time for stage 1 was higher and that for stage REM lower than for agematched normal controls (4).
Case 2
A 12-year-old girl was a full-term infant, but her mother had had a premature rupture
of membranes. The infant's weight at birth was 2,400 g. She was lethargic, hypotonic,
Sleep. Vol. 10. No.2. 1987
J
M. OKAWA ET AL.
104
TABLE 2. Type of sleep-wake rhythm and therapeutic effect in four cases
Age
Sex
Type of sleepwake rhythm
11
F
Free-running
2
12
F
Free-running
3
7
F
4
4
F
Free-running
irregular
Irregular
Case
Therapeutic measures
Forced awakening,
restricted mealtime,
phototherapy, hypnotic
drugs
Forced awakening,
hypnotic drugs
(nitrazepam)
Forced awakening,
hypnotic drugs
Forced awakening,
hypnotic drugs
Mean ± 1 SD
TST (h)
10.58 ± 0.71
(n = 55)
+
8.26 ± 1.31
(n = 53)
±
*8.56 ± 1.95
10.53 ± 2.69
(n = 51)
(n = 57)
±
8.78 ± 2.50
(n = 60)
*8.18 ± 0.89
(n = 61)
Effect
TST, total sleep time.
* Sleep-wake showed 24-h rhythm after subject took nitrazepam (case 2) or after subject grew up 2 years
(case 4). Effective (+); ineffective (-); questionable (±).
and motionless and had a weak cry. She sucked poorly and had to be fed by a dropper
at frequent intervals. Because of her poor condition, she was treated in the hospital for
2 months. Her weight at discharge was 2,900 g. Microphthalmia on the left side and
anophthalmia on the right side were noticed at birth. She responded slightly to strong
sunlight until she was 4 months of age. Since then, she has shown no response to light.
Her mental and motor development were markedly retarded: head control took 1 year;
rolling 2 years; sitting 4 years; crawling 5 years; smiling 1 year; mother recognition 2.5
years; and speaking a single word 4.5 years.
At 6 months of age, she suffered convulsive seizures at high body temperature. At 4
years of age, her mother noticed that the child slept in the day for a few weeks and then
slept at night for a few weeks. Since then, reversed sleep-wake periods had been observed several times a year. At 6 years of age, she was admitted to T University Hospital for further medical examination. She was diagnosed as having congenital malformation syndrome (microphthalmia of the left side, anophthalmia of the right side, high
arched palate, frontal prominence, retrognathia, epicanthus, simian crease, distal
triadius, and arachnodactyly). She was of short stature (Fanconi index 55.4%) and
showed joint hyperextensibility, skin hyperelasticity, and kyphosis. Psychomotor development was severely retarded, and the estimated development quotient (DQ)
was 15.
At 7 years of age, she entered a school for blind children. She usually lay on the floor
and always showed stereotypic movements such as tapping her lips with her hands and
her head with her fists. After entering school, she frequently suffered convulsive seizures accompanied by cyanosis. She began taking 0.1 g phenytoin and 0.06 g phenobarbital each day. Nurses and school teachers noticed that her sleep-onset was slightly
delayed each day so that her sleeping period drifted around the clock and back to the
starting phase within 90 days. Precise recording of sleep-wake times at 9 years of age
by nurses and nursery teachers showed a free-running rhythm of sleep-wake with an
average 24.3-h time period (Fig. 2). Total sleep time was 8.26 ± 1.31 h (mean ± SD) a
day (Table 2).
To entrain her to a 24-h rhythm of sleep-wake, she was forced to stay awake by being
kept in a sitting position, and her mealtimes were restricted. These trials had to be
Sleep. Vol. 10. No.2. 1987
'.
FREE-RUNNING RHYTHMS IN BLIND CHILDREN
105
DA Y (hrs)
12
1982
1
--I
~:IJ
FIG. 2. Double-plotted sleep-wake rhythm in a 12-yearold blind girl. Her sleep-wake rhythm was plotted for I
year on the basis of observation by nurses and school
teachers. Sleep-onset time was slightly delayed every
day. Sleep-wake cycle was reversed and was recovered
every 3 months with t = 24.27 h. During continued
forced daytime activity with daily administration of nitrazepam at a dose of 10 mg, the free-running of sleepwake was entrained to a 24-h rhythm.
-=~
~m
----"'0
I~
~~
10
~~
11
-=-<
I
~~
1;1
~I
•
.'
-J
"
discontinued, however, because of increased convulsive seizures and unexplained
bouts of fever as high as 39°C. Early in June 1982, she began taking 10 mg nitrazepam
at 1900 h each day. Simultaneously, the nursing staff began training her during the day
for activities of daily life. Two months after she began taking nitrazepam, her sleepwake pattern conformed to the 24-h rhythm (Fig. 2). The 24-h rhythm of sleep-wake
has been maintained for 4 years as of this date. Blood examinations, including liver
function test and serum electrolytes, yielded normal results. Urine screening tests for
inborn metabolic errors, such as phenylketonuria, histidinemia, galactosemia, homocystinuria, maple syrup disease, mucopolysaccharidosis, Hurtnup's disease, etc., were
negative, as was the Guthrie test.
The ERG was flat, and the brainstem-evoked responses and auditory-evoked responses were evaluated as normal. The EEG examined at 6 years of age showed an
irregular and diffuse 8- to IO-Hz activity during the waking state and 14-Hz spindles
during sleep. No distinct spike activity was noticed. The EEG examined at 9 years of
age showed spike activities in the right frontal area during the waking state and a diffuse burst of spike-and-wave complex during sleep.
Case 3
A 7-year-old girl was born prematurely. Her weight at birth as 1,750 g. Both of her
optic nerves were atrophic, and she could recognize only light and dark. At the age of
1.5 months, she began having convulsive seizures. She became bedridden. Her development was extremely retarded. Her mother noticed that at 2 years of age the child had
developed a very irregular sleep-wake rhythm.
At the age of 3 years, she was admitted to the Metropolitan Medical Center of the
Severely Handicapped. Nurses recorded her sleep-wake rhythm continuously for a
period of> 1 year through a visual observation of her behavior. She showed a free-run-
Sleep, Vol. 10, No.2, 1987
J
M. OKAWA ET AL.
106
SEP
-- -=--- -
-_
-- -
---
Aug
-=--=---=
- - -=---_
--_
.=.
OCT
~
--=- ==-..
=
- 2
S(>\l ]
"
~
"
---
-~=----::.
Oct
--
- -- -
-
=-
o
6
i
12
18
i
i
0
6
TIME OF OAY
12
-
'.
~
- - - - - ---- -i
-
----: -
:=:::::::--
i
- - - ---
---
~
-=
- --
-------- -.
1_-
NOV
OEC
=
==
--- -
_....:-:.,:-= -
18
,
o
,
0
--=-----=-=-:-----
i
i
,
6
12
18
i
----- -,
i
0
6
Tim/:' of tby
i
i
12
18
0
A
B
FIG. 3. Double-plotted sleep-wake rhythm for 4 months based on nurses' observations of a 7-year-old blind
girl. A: Free running rhythms were seen in October, November, and the first half of December. B: Forced
awakening for 1.5 months was successful in effecting a 24-h rhythm, which lasted for -I month after discontinuation of the forced awakening.
ning rhythm with periods of 25-30 h (Fig. 3A). Periodic changes of body temperature
seemed to synchronize with her sleep-wake rhythm.
After 1 year of baseline observation, entrainment of her sleep-wake rhythm to a 24-h
cycle by forced awakening was successful, but it was maintained for only ~5 weeks
after the discontinuation of forced awakening (Fig. 3B). The brain CT showed enormous dilatation of the ventricles and a low-density area in the right frontal lobe.
Polygraphic recordings during nocturnal sleep showed REM sleep and only two
stages of NREM sleep: a fast-wave stage in which fast activity of low voltage was
dominant, and another stage in which slow waves of high voltage were dominant.
There were neither sleep spindles nor vertex sharp waves. At 3 years of age, the child's
mean total sleep time by nurses' observation for 57 days was 10.53 ± 2.69 h (Table 2),
and the time-ratio of REM and NREM sleep by polygraphic recording for 1 day was
3:7, considered normal when compared with that of age-matched controls (4).
Case 4
A 4-year-old girl was a term infant with a body weight of 2,850 g at birth, but had
both congenital left anophthalmia and congenital right microphthalmia. At 1 year of age,
according to her mother, the child did not appear to have an optimal time for sleep but
seemed to sleep at indefinite times during the 24-h period. Since then, her irregular
Sleep. Vol. 10, No.2, 1987
.:
FREE-RUNNING RHYTHMS IN BLIND CHILDREN
107
sleep-wake rhythm had been continuously observed and was difficult to entrain to a
24-h rhythm despite rigid scheduling, e.g., compelling the child to keep a definite bedtime, wake-time, and mealtime.
She attended nursery school at the age of 3 years. She took naps several times in the
daytime, however, and sometimes stayed awake during the night.
She was admitted to Akita University Hospital at 4 years of age. She was 100.5 cm
tall and weighed 14.5 kg. She needed her mother's help for daily activities of life such
as eating and changing her body position even while standing. She was in the habit of
tapping her lips with her hand. She could speak several meaningful words, and sang
little songs.
Her sleep occurred at irregular intervals during the day and night, and we could not
anticipate when she was likely to sleep. The mother's precise recording of the child's
sleep-wake times at 4.5 years of age showed irregular sleep-wake rhythm with a mean
total sleep time of 8.78 ± 2.05 h (mean ± SD) each day (Fig. 4A, Table 2). The main
sleep episodes (Fig. 4) occurred between 0000 and 1200 h, which seemed to show weak
circadian rhythm of sleep-wake, i.e., small amplitude of sleep-wake rhythm. She appeared to show some partial entrainment to 24 h as well as some apparent free-running
of naps, with a period of 24.5 h. Hypnotic drugs such as nitrazepam, triazolam, or
phenobarbital were given and may have had some effects on the entrainment.
TIME OF DAY
0:00
12:00
24:00
~~~~~:=~~~~~
JUN 1984
TIME OF DAY
(hr.)
12:00
0:00
( hrs)
24:00
1986
FEB
MAR
=-
APR
MAY
A
B
FIG. 4. Single-plotted sleep-wake rhythm of case 4 for 4 months based on mother's observations. Solid bars
represent sleep. A: Although sleep episodes appeared sporadically during the day, the main sleep time was
between 0300 and 1200 h. Some apparent free-running of naps was observed in June, August, and September.
B: Twenty-four-h pattern of sleep-wake rhythm was established, especially after April.
Sleep, Vol. 10, No.2, 1987
108
M. OKAWA ET AL.
Blood examination, liver-function test, urine screening test for congenital metabolic
errors, and chromosome examination all showed normal results. The EEG showed
spikes and polyspikes in the bioccipital areas. The ERG of both eyes showed a flat
pattern, and there seemed to be no visual perception. The brain CT showed no pathological sign.
After discharge, mother and nursery teachers continued entrainment to obtain 24-h
sleep-wake rhythm using forced awakening, playing musical instruments, giving toys,
etc. Gradually, the child slept more at night than in the daytime, and her sleep-wake
rhythm seemed to be entrained to a 24-h pattern. In April 1986, at the age of 6 years,
she entered a school for blind children. By this time, she seemed to maintain a 24-h
rhythm. Furthermore, daytime school activities seemed to reinforce the 24-h sieepwake rhythm (Fig. 4B). The mean total sleep-time for 61 days in April and May 1986
was 8.18 ± 0.89 h (mean ± SD) a day.
DISCUSSION
The common characteristics in the four children were congenital blindness and
mental retardation (Table 1). Cases 1, 2, and 4 were totally lacking in light perception,
and case 3 was aware only of light and dark. For those children with such congenitally
disturbed visual function, it seems to have been difficult to synchronize the normal
24-h rhythm with the light-dark cycles in the environment. Most blind subjects, however, are able to entrain their sleep-wake rhythm stably to a 24-h day by means of
social contacts or other behavioral scheduling, e.g., bedtime, wake-time and mealtime,
and they live an ordinary social life with a 24-h rhythm. The four children presented in
this report had moderate to severe mental retardation, so that social time cues appeared too weak to act as zeitgebers.
Free-running rhythm is considered an endogenous rhythm. This has been observed
in both humans and animals under constant "time-cue-free" conditions (5-9). Under
such conditions, many human subjects exhibit an approximate 2S-h rhythm of sleepwake. The 24-h rhythm of healthy persons having an ordinary 24-h life is considered to
be regulated by synchronizing the endogenous free-running rhythm with the 24-h
rhythm in the environment. The synchronizing mechanism in humans, however, such
as the phase-response curve of the potential zeitgebers, is not well understood or optimized in most treatment attempts.
Cases 1 and 3 in the present study could not maintain a 24-h rhythm despite living in
an ordinary 24-h environment in which their mothers and teachers tried to enhance the
synchronizer by using forced awakening, playing musical instruments, or providing
tactile stimulation during the day. Thus, the sleep-wake disorders of these blind children might be due to a disordered perception of environmental time cues: Congenital
total-blindness is most unfavorable for using the light-dark cycle as a synchronizer.
Social contacts do not seem strong enough to act as a synchronizer in children having
severe to moderate mental retardation. The disorders may also be due to the inadequate intrinsic resetting capacity of the circadian pacemaker.
In animal experiments, after either enucleation of both eyes or transection of the
optic nerves, entrainment to the light-dark cycle no longer occurred, and the rest-activity cycle showed a free-running rhythm either with a normal light-dark cycle or in
constant darkness (10,11). The free-running rhythm observed in our children may have
been formed in a similar situation.
Sleep, Vol. 10, No.2, 1987
'.
FREE-RUNNING RHYTHMS IN BLIND CHILDREN
109
When the pacemaker (SCN) was destroyed in animal experiments, leaving visual
neural connections intact, some persistent irregular clustering of activity was observed
during the dark phase of a light-dark cycle (masking effect), but in constant darkness
there was virtually complete loss of circadian rhythmicity. In contrast, when the optic
tracts were destroyed behind the optic chiasm, entrainment to the light-dark cycle persisted although the animal was behaviorally blind (10). When the animal was placed in
constant darkness, however, there was normal free-running rhythm, demonstrating
that the pacemaker remained intact. Thus, SCN is considered a pacemaker of the freerunning rhythm. From this, it may be inferred that cases 1-3, in showing persistent
free-running rhythms, have intact pacemakers.
For a few years after case 4's birth, her irregular sleep-wake rhythm was considered
a manifestion of arrhythmic sleep-wake rhythm caused by damage to the central
nervous system. We systematically studied biological rhythms in severely brain-impaired children to elucidate the biological clocks in humans (12-16). We reported that
the brain stem tegmentum may play an important role in developing the sleep-waking
rhythm (13,15,16). The brainstem in case 4 seemed intact, however, according to the
results of neurological examinations, including CT scans.
During the maturation period in infancy, the circadian rhythms of sleep-wake, body
temperature, urine excretion, etc., developed in the course of progressive increase in
amplitude (17). Similar studies over the first 6 months of life by Kleitman and Englemann (18) indicate that the proportion of time awake during the day steadily increases
and the proportion during the night diminishes, demonstrating the increased amplitude
of sleep-wake rhythm in the developmental process. In this study, free-running rhythm
was observed from -8 to 14 weeks of age, before a 24-h rhythm developed. Based on
these studies case 4 in the present study was considered to have late development of
circadian sleep-wake rhythm. Because she gradually assumed the 24-h sleep-wake
rhythm by the time she entered school, her pacemaker is intact and her irregular sleepwake rhythm may be due to immaturity of the pacemaker of the circadian rhythm in
the brain and/or due to weak perception of social cues in her environment because of
mental retardation.
Free-running rhythm was observed in a blind student who had normal intelligence (2)
as well as in normally sighted persons who lived in a normal 24-h environment (19,20).
In these cases, the endogenous circadian rhythm was preserved. It is possible, however, that the mechanism used for entraining the endogenous circadian rhythm of the
subjects to the 24-h period of the external environment was disturbed. Case 4 in our
study indicates that the mechanisms of entrainment may be different from those that
amplify the rhythm. Detailed morphological investigations must be performed for a
further understanding of human biological clocks.
REFERENCES
1. Czeisler CA, Richardson GR, Zimmerman JC. Entrainment of human circadian rhythms by light-dark
cycles: are-assessment. Photochem Photobiol 1981 ;34:239-47.
2. Miles LEM, Raynal DM, Wilson MA. Blind man living in normal society has circadian rhythms of 24.9
hours. Science 1973;198:421-3.
3. Miles LE, Wilson MA. High incidence of cyclic sleep wake disorders in the blind. Sleep Res 1977;6: 192.
4. Williams RL, Karacan I, Hursch GJ. EEG of human sleep: clinical applications. New York, Wiley, 1974.
5. Aschoff J. Circadian rhythm in man. Science 1965;148:1427-32.
6. Chouvet G, Mouret J, Coindet J, et al. Periodicite bicircadienne de cycle veille-sommeil dans des conditions hors de temps. Elecroencephalogr Clin NeurophysioI1974;37:267-380.
7. Weitzman ED, Czeisler CA, and Moore-Ede MC. Sleep-wake, neuroendocrine and body temperature
Sleep, Vol. 10, No.2, 1987
M. OKAWA ETAL.
110
8.
9.
10.
II.
12.
13.
14.
15.
16.
17.
18.
19.
20.
circadian rhythms under entrained and nonentrained (free-running) conditions in man. In: Suda M,
Hayaishi 0, Nakagawa H (eds.), Biological rhythms and their centrai mechanism. Amsterdam: Elsevier/North-Holland Biomedical Press, 1979:199-277.
Mills IN. Circadian rhythms during and after three months in solitude under ground. J Physiol (Lond)
1964;174:217-31.
Richter CPo Sleep and activity: their relation to the 24-hour clock. Proc Assoc Res Nerv Ment Dis
1967;45:8-27.
Rusak B. The role of the suprachiasmatic nuclei in the generation of circadian rhythms in the golden
hamster, mesocricetus auratus. J Comp PhysioI1977;118:145-64.
Stephan FK, Zucker I. Rat drinking rhythms; central visual pathways and endocrine factors mediating
responsiveness to environmental illumination. Physio/ Behav 1972;8:315-26.
Okawa M, Sasaki H, Nakajima S, Takahashi K. Altered sleep rhythm: a patient with a 10 to 15 day cycle.
J Neurol 1981 ;226:63-71.
Okawa M, Sasaki H. Disorders of sleep-waking rhythm-a report of three cases. Adv Neurol
1981 ;25: 1164-75.
Okawa M, Sasaki H, Takahashi K. Disorders of circadian body temperature rhythm in severely braindamaged patients. ChronobiolInt 1984;1:67-71.
Okawa M. Sleep-waking rhythm and its central mechanism in human: studies of biological rhythm,
computed tomography and autopsy of severely brain-damaged children. Adv NeuroI1985;29:346-65.
Okawa M, Takahashi K, Sasaki H. Disturbance of circadian rhythms in severely brain-damaged patients
correlated with CT findings. J Neurol 1986;233:274-82.
Hellbrugge T, Lange TE, Rutenfranz J, et al. Circadian periodicity of physiological functions in different
stages of infancy and childhood. Ann NY Acad Sci 1964;1l7: 361-73.
Kleitman N, Engelmann TG. Sleep characteristics of infants. J Appl PhysioI1953;6:269-82.
Weber AL, Cary MS, Connor N, et al. Human non-24-hour sleep-wake cycles in an everyday environment. Sleep 1980;2:347-54.
Kokkoris CP, Weitzman ED, Pollak CP, et al. Longterm ambulatory temperature monitoring in a subj~ct
with a hyper-nychthemeral sleep-wake cycle disturbance. Sleep 1978;1:177-90.
Sleep, Vol. /0, No.2, 1987