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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.