Download Periodic leg movement, sleep fragmentation and central sleep

SHORT REPORT
Eur Respir J
1988,1,762-765.
Periodic leg movement, sleep fragmentation and central sleep
apnoea in two cases: reduction with Clonazepam
C. Guilleminault, C. Crowe, M.A. Quera-Salva, L. Miles, M. Partinen
Periodic leg fll()venuml, sleep fragmentation and central sleep apnoea in two
cases: reduction with Clonazepam. C. Guilleminault, C. Crowe, MA. QueraSalva, L. Miles, M. Partinen.
ABSTRACT: Two subjects presented with periodic leg movement (PLM)
syndrome during sleep that was characterized by marked sleep fra2mentatlon and repetitive short central apnoeas. Treatment of PLM using
Clonazepam, a benzodiazepine with hypnotic properties, markedly reduced the sleep fragmentation due to PLM and, despite it~ depressant
properties on the central nervous system, controUed the repetitive central apnoeas. These two observations, although rare, give Insight into the
role of non-ventilatory variables in the development of sleep apnoea.
Significant sleep fragmentation should be considered when assessing factors leading to respiratory Instability during sleep and/or the pathophysiology of sleep apnoea syndromes.
Eur Respir J .• 1988. 1. 762-765.
Periodic leg movement (PLM) syndrome during sleep
was ftrst described in 1953 by SYMONDs (1], who called
it "nocrurnal myoclonus" and distinguished it from the
jerks occasionally experienced by normal individuals
upon falling asleep. The phenomenon is a sleep-related
problem involving repetitive, stereotypic discharges of
varying intensity in the anterior tibialis muscles, leading to the extension of the big toe. The ankle, knee,
and sometimes the hip may flex after the toe has been
extended. The phenomenon presents itself as the classic abnormal plantar response or Babinski sign that is
elicited by stroking the lateral aspect of the sole during wakefulness [2]. The jerks are generally bilateral
but may randomly involve a single leg. There is generally an interval of 20-40 s between events, which
occur in clusters varying in length from 10 minutes to
several hours, and in some patients, last throughout
nocturnal sleep [3-5]. Classically, PLMs are more frequent during stages 1 and 2 non-rapid eye movement
(NREM) sleep and tend to attenuate during rapid eye
movement (REM) sleep.
The cause of PLM syndrome is still unknown and
many treatments have been tried. Clonazepam, a benzodiazepine; Baclofen; and, more recently, L-dopa with
dopa-decarboxylase inhibitor [6, 7] have produced
promising results. CoLEMAN [5] demonstrated frequency
of PLM in obstructive sleep apnoea syndrome (OSAS)
patients, when it was often associated with the onset
of unobstructed breathing. This presentation reports on
the role of PLM in the frequency of central apnoea in
two subjects.
Correspondence: C. Guillcminault, Sleep Disorders Center, Stanford University School of Medicine, 701 Welch Road, Suite 2226, Palo Alto, CA
94304, USA.
Keywords: Central sleep apnoea; Clonazcpam; sleep
fragmentation; obstructive sleep apnoea syndrome;
periodic leg movement.
Received: September 21, 1987; accepted after revision April 28, 1988.
This woric was supported by grant AG 06066 from
the National Institute of Ageing.
Patients and methods
Case reports
Two patients, a 42-year-old man (patient 1) and a 48ycar-old woman (patient 2), with body mass index
(BMI) of 25 and 23, respectively, were referred with
marked insomnia. Past medical history was non-significant: patient 2 had a tonsillectomy in childhood and
smoked for three years in her early twenties. Neither
patient used alcohol regularly, having at most one glass
of wine every 15-30 days. Both complained of nocturnal sleep disturbances consisting of short sleep
latencies at sleep onset, frequent awakenings during
sleep, and a feeling of daytime fatigue for a minimum
of five and eight years, respectively. Each had
previously received hypnotic medications with transient
improvements, but neither had taken any drug during
the four months prior to consultation. Spouses confirmed that the patients manifested frequent leg jerks,
very restless sleep, and the presence of apnoea without
snoring. Clinical evaluation had been non-contributive;
chest roentgenograms, 12-lead ECG, supine, awake
blood gases, and blood tests (electrolytes, glucose, etc.)
were within the normal laboratory limits. A clinical
neurological evaJuntion was negative, and 4-limb electrmyogram and nerve conduction studies were normal.
Cephalometric roentgenogr<~ms showed no abnormal
crania-mandibular features.
C. GUILLEMINAULT ET AL.
763
arousal was noted [9). If apnoea was present, its type
was defined. We calculated an apnoea index (apnoeas
per hour of sleep), defined as number of apnoeas x 60
per total sleep time (TST) in min. and a PLM index
(PLMs per hour of sleep), defined as number of PLMs
x 60 per TST in min.
Protocol
Each patient underwent three nights of baseline polygraphic monitoring. The monitored variables included
electroencephalogram (EEG) (C3/A2 - C4/A1 derivations from the 10-20 imemational placement system),
electro-oculogram (EOG), chin electromyogram (EMG),
electrocardiogram (ECG with modified V2 lead), left
and right anterior tibialis EMG. Respiration was
monitored by non-calibrated inductive respiratory
plethysmography, nasal and buccal thermistors and ear
oximetry (Biox Ill). An oesophageal balloon was also
used on the third baseline night. Polygraphic monitoring started between 22.00 and 22.30 h. MoniiOring
ended when patients decided to get up, although they
were encouraged to stay in bed for as long as possible.
On the two nights following completion of the
nocturnal baseline moniiOring, patients received 0.5 mg
of Clonazepam at bedtime and were again monitored.
Patients were then sent home for 1 week and instructed
to take one mg of Clonazepam each night at bedtime.
After the week of increased dosage, patients returned
to the clinic for a final night of monitoring. All
procedures conformed to guidelines established by the
university's committee on ethics.
Results
The very significant sleep disruption and fragmentation coincided with a combination of leg movements
and central apnoeas (table 1). Since missed breaths of
<10 s duration were not considered "apnoeas," there
were actually more than were tabulated. Apnoeas tended
to be short, with mean duration of 13 and 15 s, respectively, for patients 1 and 2 on baseline nights 1 and 2.
The lowest oxygen saturation (Saoz) drop was 92% in
both cases. On baseline night 3, placement of the oesophageal balloon caused a significant increase in long
awakenings after onset of sleep and led patients with
significant sleep disturbance to complain of nose and
throat irritation. During night 3, however, sleep segments demonstrated the central apnoeas noted during
monitoring the two previous nights.
Our small sample did not permit valid statistical
analysis, but 0.5 mg of Clonazepam at bedtime and,
more importantly, 1 mg dosages allowed maintenance
of sleep associated with significant decrease in arousals,
PLM, and central sleep apnoeas (table 1). The apnoea
index (AI) dropped from a mean of 60 and 36 (patients
1 and 2) on baseline nights 1 and 2 to 13 and 8 with
Analysis
Records were scored following the international
manual of R.ECHTSCH.AFFEN and l<ALES (8). Each periodic
leg movement was identified and any alpha EEG
Table 1.- Patient data from nocturnal monitoring
XTRT
min
XTST X%
min
REMS
PLM
n
PLM
w/alpha
arousal
AI
%
central
apnoea
PLM
Index
PLMw/alpha % S-1
arousal Index
%S-2
% REMS
n
----------------------------- -----------------------------------------
Baseline X nights 1 and 2
patient 1
patient 2
465
481
178
235
4
7
65
100
1.2
3
220
450
100
215
60
36
>95
>95
74
114.9
33.7
54.9
63
68
33
25
4
7
40
79
37
59
20
39
>95
>95
36.9
47.4
34
9.8
82
84
16.7
13
1.2
3
12
14
85
76
41
20
13
>95
8
>95
13.8
12.3
6.6
3.2
10
8.8
78
77
12
14.2
13
14.5
20
42
7
11
9
>95
4
>95
3.4
6.6
1.2
1.7
8
5
79
80.5
13
14.5
Baseline night 3
patient 1
patient 2
361
350
Clonaz.epam 0.5 mg
patient 1
patient2
472
486
X nights 4 and 5
309
37 1
Clonaz.epam 1 mg X night 14
patient 1
patient2
439
462
351
379
Baselinenight3: As mentioned in the text, patients were monitored with oesophageal balloon, which greatly disturbed the already
exist~g poor sleep. This added sleep disturbance explains the differences !_!Oted between baseline nights 1 and 2 and night 3.
TST IS greatly reduced, and sleep-related parameters are thus artificially low. X: mean; TRT: total recording time; TST: total sleep
time; PLM: periodic leg movement; Al: apnoea index; S-1: stage 1 NREM sleep; S-2: stage 2 NREM sleep;% REMS: percentage of
REM sleep during TST.
764
SLEEP APNOEA AND PERIODIC LEG MOVEMENT
0.5 mg Clonazepam. The PLM index dropped from 74
and 114.9 on baseline nights to 13.8 and 12.8, respectively. The improvement was even more pronounced
with 1 mg clonazepam, with an apnoea index of 9
and 4 and a PLM index of 3.4 and 6.6, respectively,
for patients I and 2. These changes in apnoea index and
PLM index were associated with a decrease in the percentage of stage 1 NREM sleep and an increase in the
percentage of stage 2 NREM and REM sleep during
TST.
Discussion
The two patients studied were of interest, presenting
with significant sleep reduction, marked sleep fragmentation, and a combination of PLM and multiple
repetitive central breathing irregularities. It is unclear
from the baseline recordings whether PLM syndrome or
breathing irregularities was primarily responsible for the
significant sleep disturbance. Considering the normal
daytime clinical evaluation and test results, the very
limited and rare Sao2 drops seen with the central
apnoeas, and the importance of PLM associated with
alpha arousal and awakenings, we hypothesized after the
first recording that the significant sleep fragmentation
with continuous wake-sleep-wake shift was responsible
for the breathing irregularities. Because PLM syndrome
contributed significantly to the sleep fragmentation, we
selected a hypnotic drug (despite its depressant effects
on the central nervous system) previously used in
the treatment of PLM syndrome. The resulting marked
reduction in PLM and sleep fragmentation led to a
near-normal breathing pattern during sleep and normal
passage to deeper stages of sleep. These observations
have to be related to the recently published absttact by
BoNNET et al. (10] on the effect of Triazolam in increasing sleep continuity and decreasing the number of central sleep apnoeas in healthy elderly subjects. ONAL et
al. [11] have hypothesized that obslructive sleep
apnoea may develop in patients presenting marked
respiratory oscillations during sleep. Our observations,
and those of BoNNET et al. [10] indicate that sleep fragmentation will lead to "missed breath" (central
apnoeas), and that better maintenance of sleep, related
here to a decrease in the number of PLMs, will eliminate these apnoeas. The drop from Ais of 60 and 36
to 9 and 6, respectively, with 1 mg of Clonazepam was
striking. This reduction in apnoea frequency was obtained despite the fact that stages 1 and 2 NREM sleep
still represented 87 and 85% of TST respectively.
Stages 1 and 2 NREM sleep are the two stages during
which both respiratory oscillations and PLM are normally observed.
Very little data are currently available on the development of repetitive sleep apnoeas. Recently, IssA and
SULLIVAN (12), GUILLEMINAULT et al. (13), and
HoFFSTEIN et al. [14] reported on the impact of nasal
continuous positive airway pressure (CPAP) on central
sleep apnoea, and the association of upper airway anatomical abnormalities. We have also reported observa-
tions in children [15] and adults [16], with anatomical
abnormalities of the upper airway, where central
apnoeas preceded by months or years the monitoring of
mixed and obstructive apnoeas. The two cases reported
clearly demonslrate that elimination of sleep fragmentation induced by PLM greatly improves the maintenance of normal air exchange during sleep despite the
added effect of a benzodiazepine. Models considering
onset of "respiratory oscillations" during sleep give the
primary role to ventilatory variables, particularly
changes in blood gases as seen in sleep-related periodic
breathing at high altitude (17], or cluster of hyperventilatory breaths at time of arousal (which decrease
carbon dioxide tension Pco2 and drive it below the
"apnoeic threshold" during sleep) in some mixed sleep
apnoeas [18]. But no cluster of hyperventilatory breaths
at time of arousal, or significant increase in positive and
negative pressure measurement with an oesophageal
balloon was noted here.
Our two case reports indicate that non-ventilatory
variables, in this case sleep fragmentation, can be the
primary element in repetitive abnormal breathing patterns during sleep. A systematic evaluation of one hundred successive male obstructive sleep apneic patients
has shown that 39 presented with PLM not influenced
by nasal CPAP [19]. Another study, performed on a
smaller group of subjects, produced similar findings
[20]. The role of sleep fragmentation in disturbing
hypoxic and hypercapnic responses has been well
demonsttated in animal studies [21]. However, its
potential role in induction of periodic ventilatory problems in humans and the development of cenlral sleep
apnoea is difficult to demonsttate. The two subjects
reported were rare, but observation of them gave us
insight into the different mechanisms, ventilatory and
non-ventilatory, that can be involved in the development
and maintenance of sleep apnoea.
Acknowledgements: We thank B. Ha yes and D. Cobasko for
providing technical assistance and A. Grant for editing the
manuscript.
References
1. Symonds CP. - Nocturnal myoclonus. J Neural NeuroSurg
Psychiatry, 1953, 16, 166- 171.
2. Smith RC. - Relationship of periodic movements in sleep,
(nocturnal myoclonus) and the Babinski sign. Sleep, 1985, 8,
239- 243.
3. Lugaresi E, Coccagna G, Berti-Ceroni G, et al. - Restless legs syndrome and nocturnal myoclonus. In: The Abnormalities of Sleep in Man; Proceedings of the 15th European
Meeting on Electroencephalography, Bologna, 1967. H Gastaut, E Lugaresi, G Berti-Ceroni, G Coccagna eds, Bologna:
Aulo Gaggi Editore, 1968, pp. 285-294.
4. Guilleminault C, Raynal D, Weitzman ED, et al. - Sleeprelated periodic myoclonus in patients complaining of insomnia. Tran.s Am Neural Assoc, 1975, 100, 19-21.
5. Coleman RM. - Periodic movements in sleep (nocturnal
myoclonus) and restless leg syndrome. In: Guilleminault C
(ed). Sleeping and Waking Disorders: Indications and Techniques. Menlo Park, CA. Addison-Wesley, 1982, pp. 265-296.
6. Montplaisir J, Godbout R. Poirier G, Be'dart MA. - Rest-
C. GUILLEMINAULT ET AL.
less legs syndrome and periodic movements in sleep, physiopathology and treatment with L-dopa. Neuroclin Pharmacol,
1986, 5, 456-463.
7. Guilleminault C, Mondini S, Montplaisir I, Mancuso I,
Cobasko D. - Effect of 5-HTP, L-dopa and dopa decarboxylase inhibitor on periodic leg movement Sleep, 1987, 10,
393-397.
8. Rechtschaffen A, Kales A. - In: A manual of standardized terminology, Techniques and scoring system for sleep
stages of human subjects. Brain Information Service/Brain
Research Institute, UCLA, Los Angeles, 1968.
9. Coleman RM. - Periodic movements in sleep (nocturnal
myoclonus) and restless leg syndrome. In: Sleep and Waking Disorders: Indications and techniques. C. Guilleminault
ed., Addison-Wesley, Menlo Park, CA, 1982.
10. Bonnet MH, Dexter IH, Arand D. - The effect of
Triazolam in increasing continuity in patients with central
sleep apnea. Sleep Res, 1987, 16, 310 (abstract).
11. Onal E, Lopata M. - Periodic breathing and the pathogenesis of occlusive apnea. Am Rev Respir Dis, 1982, 126,
676-680.
12. Issa FG, Sullivan CE. - Reversal of central sleep apnea
using nasal CPAP. Chest, 1986, 90, 165-171.
13. Guilleminault C, Quera-Salva MA, Nino-Murcia G, Partinen M. - Central sleep apnea and partial obstruction of the
upper airway. Ann Neurol, 1987. 21, 465-469.
14. Hoffstein V, Slutsky AS. - Central sleep apnea reversed
by continuous positive airway pressure. Am Rev Respir Dis,
1987, 135, 1210- 1212.
15. Guilleminault C. - Diagnosis, pathogenesis, and treatment
of the sleep apnea syndromes. In: Advances in Internal
Medicine and Pediatrics, vol. 52. Stuttgart: Springer-Verlag,
1984, pp. 1-57.
16. Guilleminault C, Riley R, Powell N. - Development of
sleep apnea in normal subjects following mandibular osteot-
765
omy with retrusion: two case histories. Chest, 1985, 88,
776-778.
17. West JB. Lahiri S eds. - High Altitude and Man. Bethesda: Clinical Physiology Series, American Physiological
Society, 1981.
18. Dempsey JA, Skatrud IB. - A sleep induced apneic
threshold and its consequences. Am Rev Respir, Dis 1986,
133, 1163- 1170.
19. Guilleminault C, Crowe C, Quera-Salva MA. Partinen M,
Miles L, Nino-Murcia G. - Periodic leg movements (PLM)
and sleep apnea. Sleep Res. t 987, 16, 341 (abstract).
20. DiPhillipo MA. Pressman MR. Fry JM. - Disruption of
sleep by previously occult periodic leg movements in sleep
following successful tteatment of sleep apnea syndrome with
nasal CPAP. Sleep Res. 1987, 16, 325 (abstract).
21. Phillipson EA. Bowes G. SuUivan CE, Woolf GM. - The
influence of sleep fragmenta tion on arousal and ventilatory
responses to respiratory stimuli. Sleep, 1980, 3, 281- 289.
RESUME: Deux sujets, pr~entant simultanement un syndrome des mouvements periodiques des jambes et apnees
centralcs repetees lors du sommeiJ, sont rapportes. Tous deux
presentaient une fragmentation importante du sommeil. Une
benzodiazepinc ~ effet hypnotique. le clonazepam, normalement prescrite oomme traitement des mouvements periodiques,
fut essayee, malgre le risque de depression du control central de la ventilation. La fragmentation du sornmeil l'ul considerablement diminuee apres amelioration des mouvements
periodiques, et les apnees centrales se firent rare. Ces deux
observations mettent bien en evidence le role des facteurs non
li~ ~ la ventilation dans la genese des apnees du sommeil.
Le role de la fragmentation du sommeil doit etre systematiquemenl oonsidere, lors de !'analyse des facteurs inductifs
d'instabilite respiratoire lors du sommeil et lors de !'etude de
Ja pathophysiologic du syndrome d'apnees du sommeil.