S108 Clinical Neurology and Neurosurgery, 94 (Suppi.)(1992) S108- SllO Q 1992 Elsevier Science Publishers B.V. All rights reserved 0303~8467/92/$OS.OO
CNN 00135
The Multiple Sleep Latency test: a paradoxical test? G.J. Lammers and J.G. van Dijk Department of Neurology and Clinical Neurophysiology, UniversityHospital, Leiakn (The Netherlands)
Z&y wmzk
Subjective sleepiness; Narcolepsy; Multiple Sleep Latency test; Maintenance of wakefulness test
Summary
The Multiple Sleep Latency Test (MSLT) has gradually gained acceptance as an objective equivalent of the complaint of sleepiness. The history of this test and questions considering the validity of the MSLT in different situations are discussed. Introduction
Discussion
Research in the field of sleep and excessive daytime somnolence (EDS) has shown an impressive growth in the last decades, which has resulted in a rapid progression of our knowledge of these phenomena. As in most scientific research, the basis upon which this knowledge was built was the establishment of valid quantitative measurements. This was and is especially important for EDS since sleepiness is essentially a subjective feeling, which can otherwise only be assessed by subjective ratings with its well-known limitations. In sleep research one of the most important milestones was the application of the EEG, which first led to the discovery of REM sleep [l] and which later resulted in the classification of the various sleep stages [2]. The most important improvement for the study of EDS (and narcolepsy, which is among others characterized by EDS) was the introduction of the Multiple Sleep Latency Test (MSLT). This test has gained acceptance as the first objective test for quantification of sleepiness [3]. The question we wish to address in this paper is how well the MSLT functions as an objective test for an essentially subjective complaint: sleepiness. Can the MSLT be used equally well in healthy subjects as in patients with EDS, and can it be used diagnostically as well as for the assessment of therapeutic efficacy?
The MSLT was introduced in 1977 [4] and standardized and generally accepted in 19% [3]. It eon&s of the measurement of the sleep latency in each of five 2Omin periods divided over the day, in which persons are asked to lie down on a bed in a dark ad quiet room and to try to fall asleep. Besides measuringsleep onset, sleep stages are determined, with special attention for the occurrence of (multiple) sleep unset REM periods. If the mean sleep latency of all five naps is less than IO tin, one speaks of EDS. Severe hypersomnia is defined by a mean latency less than 5 min. Values of over 10 min are considered normal. The capability of the MSLT to measure sleepiness was established by applying the test to a group of healthy volunteers who were deprived of sleep to different degrees. Significant correlations between the severity of deprivation and sleep latency the next day were found. There was, moreover, a significant correlation between subjective sleepiness scores and sleep latencies [WJ]. So the conclusion was drawn that sleep iatencies represented objective quantitative scores of sleepiness. Furthermore, a significant correlation between certain clinical syndromes associated with EDS and MSLT iindings turned out to exist [9,10]. Among others this held for the occurrence of sleep onset REM periods in narcolepsy [3,11,12]. For these reasons it was concluded that the MSLT could be taken as an objective test for the diagnosis of EDS, and for narcolepsy as well. Because of these validated properties, the MSLT has gained widespread acceptance. Grad&y studies were published in which the MSLT was used as an objective
Correspondence to: Dr. G.J. Lammers, Department of Neurology and Clinical Neurophysiology, University Hospital P.O. Box 9600,230O RC Leiden, The Netherlands. Tel.: (71) 262111/262104.
s109 test for the evaluation of the efficacy of some generally accepted drugs [7] and new drugs [13-161 in the treatment of narcolepsy. In none of these studies was a significant improvement of sleep latencies reached. So for all these drugs the conclusion was reached that there was no objective improvement of sleepiness; as a consequence most of these drugs were considered as not useful for the treatment of EDS in narcolepsy. Interestingly an exception was made for dexamphetamine and pemoline because those drugs were already generally accepted as useful on clinical grounds. Moreover, MSLT data of the other generally used drugs seem not to exist [17]. Possibly because of these somewhat disappointing results several new objective tests have been proposed, the only other direct test for sleepiness being the Maintenance of Wakefulness Test (MWT) [7,18]. This test resembles the MSLT, but patients are not asked to sleep but arc in contrast asked to sit down in a chair and to try to stay awake. This test has not yet become generahy accepted, and conflicting results in the assessment of treatment effects have been described [7,19-X]. Even the generally as potent accepted drugs for the treatment of sleepiness in narcolepsy (methylphenidate, pemoline and amphetamine) showed in only one study and not consistent with the used dose a small improvement of sleep latency in the MWT [20]. In addition, more indirect objective tests for the measurement of sleepiness are used: pupillography, event-related potentials, temperature measurement and psychophysiological concentration and reaction time tests, etc. [22-251. Some of these tests were described without a validation of their capability of measuring sleepiness in narcolepsy. In spite of this, if a drug showed an improvement on one of these tests, the conclusion was drawn that such a drug resulted in an objective improvement of sleepiness [20,26]. For this reason one gets the suggestion that finding an improvement of objective sleepiness might in fact be related to parameters of the chosen test rather than to the potency of the drug under investigation. This leads us to a situation where the very drugs, which are considered as the most potent in the treatment of sleepiness in narcolepsy, do in fact not result in an improvement of what is considered the most reliable test for sleepiness. In addition, their effect on the MWT is slight. How can we explain these seemingly contradictory properties of the MSLT (and MWT)? Some explanations of the MSLT’s paradoxical nature have already been considered [7,27]: sleepiness is a combination of several different subjective feelings, of which the MSLT may only measure one; the MSLT is not sensitive enough in narcolepsy; EDS patients suffering of chronic sleepiness are not able to score subjective sleepiness reliably anymore; requiring a patient to fall asleep
may be an inaccurate reflection of the ability of a drug to evoke the exactly opposite effect, i.e. to keep the patient awake. We consider another possibility. Falling asleep does not only involve feeling sleepy, but also changing from the waking to the sleeping state. The ability to change states may differ between healthy and diseased subjects. In fact, an important pathophysiological theory in narcolepsy is based on this: this is called a disturbance of the ‘state boundary control’ [28]. In this theory it is considered impossible for narcoleptic drugs to remain in a certain wake or sleep-stage for protracted periods. Moreover, dissociation of phenomena which normally occur together can be seen, such as the occurrence of muscle atonia in cataplexy; normally, atonia occurs only during REM sleep. As a consequence of disturbed boundary control one may assume that, in narcolepsy, stage transitions occur relatively independent of sleepiness and very short sleep latencies are therefore likely to occur. If for instance a drug does alleviate (subjective) sleepiness substantially, but does not improve the disturbed ‘state boundary control’, then the MSLT-latencies may remain as short as they were before. According to this theory the MSLT can indeed function as an important objective test for the diagnosis of narcolepsy, as it mainly measures ‘state boundary control’ in this disease. But it then is of minor value as an objective quantitative test for sleepiness in narcolepsy, since this is only partly reflected in sleep latencies. Analogous, the MWT does not perform well in the measurement of sleepiness. It, however, is more sensitive to treatment effects on sleepiness, because not only sleepiness and boundary control, as in the MSLT, influence the capability to stay awake. Motivational factors are of influence as well and may be influenced by certain drugs resulting in a second stimulant to keep awake as is measured during this test. Further research must verify this theory of the impact of multiple phenomena on sleep latency and elucidate which component (sleepiness or boundary control) is more important in narcolepsy. In the meantime the problem which test is best suited to measure sleepiness remains unanswered. When MSLT sleep latencies are simply regarded as equal to subjective sleepiness, then a failure of a drug to improve sleep latencies may falsely be taken to mean that the drug does not work. In effect there have been instances where a drug did improve subjective sensation of sleepiness without affecting sleep latencies [7,14,16,21]. Moreover, there is compelling evidence (Lammers, unpublished observation) that the relationship between subjective sleepiness and sleep latencies that exists in healthy subjects changes profoundly in narcoleptic drugs, underlining that the one may not be substituted for the other.
SllO
Conclusion The conclusion seems inescapable that, for the evaluation of treatment effects in narcolepsy, it is better to use subjective sleepiness scores than indirect approximations of sleepiness, which may be objective, but which measure other phenomena as well. After all, this subjective feeling is the complaint of the patient that we, as doctors, are supposed to alleviate. References Aserinsky E, Kleitman N. Science 1953; 118: 273-274. Rechtschaffen A, Kales. Brain Information Selvice/Brain Research Institute, UCLA, 1968. Cat&radon MA, Dement WC, Roth T, Westbrook PR, Keenan S. Sleep 1986; 9: 519-524. Carskadon MA, Dement WC. Sleep Res 19n 6: 200. Calskadon MA, Dement WC. Psychophysiology 1977; 14: 127-133. Carskadon MA, Dement WC. Percept Motif Skills 1979; 48: 495506. Hartse KM, Roth T, Zorick FJ. Sleep 1982; 5: S107S118. Roth T, Roehrs T, Zorick A. Sleep 1982: Sl28-SlW. Roth T, Hartse KM, Zorick F, Conway W. Sleep 1980; 3: 425-439. 10 Richardson GS, Carskadon MA, Flagg W, van den Hoed J, Dement WC, Mitler MM. Electroenceph Clin Neurophysiol 1978; 4.5: 621627.
11 Mitler MM, van den Hoed J, Carskadon MA, et al. Electroenceph Clin Neurophysiol 1979; 46: 479-481. 12 Carskadon MA, Dement WC. Neurosci Behav Rev 1987; 11: 307317. 13 Scrims L, Hartman PG, Johnson FH, Thomas EE, Hiller FC. Sleep 1990; 13: 479-490. 14 Lammets GJ, Arends J, Declerck AC, Kamphuisen HAC, Schouwink G, Troost J. Sleep 1991; 14: 130-132. 15 Boivin DB, Montplaisir J. Neurology 1991; 41: 1267-1269. 16 Guilleminault C, Mancuso J, Salva MAQ, et al. Sleep 1986; 9: 275-279. 17 Lammers GJ, van Dijk JG, Arends J, et al. New Engl J Med 1991; 324: 271. 18 Mitler MM, Gujavarty KS, Browman CP. Electroenceph Clin Neurophysiol 1982; 53: 6.58-661. 19 Mitler MM, Shafor R, Hajdukovich R, Timms RM, Browman CP. Sleep 1986; 9: 260-264. 20 Mitler M, Hajdukovic R, Erman M, Koziol JA. J Clin Neurophysiol 1990; 7: 93-118. 21 Fry JM, Pressman MR, DiPhilippo MA, Forst-Paulus M. Sleep 1986; 9: 269-274. 22 Yoss RE, Moyer NJ, Ogle KN. Neurology 1969; 19: 921-928. 23 Wilkinson R In: Abt L, Reiss B (eds.), Progress in Clinical Psychology. New York: Crune & Stratton, 1968: 2%%3. 24 Pressman MR, Fry JM. Sleep 1989; 12: 239-245. 25 Aguirre M, Broughton RT. Electroenceph Clin Neurophysiol1987: 67: 298-316. 26 Meier-Ewert K, Matsubayashi K, Benter L. Sleep 1985; 8: 95-104. 27 Carskadon MA, Dement WC. Sleep 1982; 5: S67s72. 28 Broughton RJ, Valley V, Aquirre M, Roberts J, Suwalsky W, Dunham W. Sleep 1986; 9: 205-215.
CNN 00135
The Multiple Sleep Latency test: a paradoxical test? G.J. Lammers and J.G. van Dijk Department of Neurology and Clinical Neurophysiology, UniversityHospital, Leiakn (The Netherlands)
Z&y wmzk
Subjective sleepiness; Narcolepsy; Multiple Sleep Latency test; Maintenance of wakefulness test
Summary
The Multiple Sleep Latency Test (MSLT) has gradually gained acceptance as an objective equivalent of the complaint of sleepiness. The history of this test and questions considering the validity of the MSLT in different situations are discussed. Introduction
Discussion
Research in the field of sleep and excessive daytime somnolence (EDS) has shown an impressive growth in the last decades, which has resulted in a rapid progression of our knowledge of these phenomena. As in most scientific research, the basis upon which this knowledge was built was the establishment of valid quantitative measurements. This was and is especially important for EDS since sleepiness is essentially a subjective feeling, which can otherwise only be assessed by subjective ratings with its well-known limitations. In sleep research one of the most important milestones was the application of the EEG, which first led to the discovery of REM sleep [l] and which later resulted in the classification of the various sleep stages [2]. The most important improvement for the study of EDS (and narcolepsy, which is among others characterized by EDS) was the introduction of the Multiple Sleep Latency Test (MSLT). This test has gained acceptance as the first objective test for quantification of sleepiness [3]. The question we wish to address in this paper is how well the MSLT functions as an objective test for an essentially subjective complaint: sleepiness. Can the MSLT be used equally well in healthy subjects as in patients with EDS, and can it be used diagnostically as well as for the assessment of therapeutic efficacy?
The MSLT was introduced in 1977 [4] and standardized and generally accepted in 19% [3]. It eon&s of the measurement of the sleep latency in each of five 2Omin periods divided over the day, in which persons are asked to lie down on a bed in a dark ad quiet room and to try to fall asleep. Besides measuringsleep onset, sleep stages are determined, with special attention for the occurrence of (multiple) sleep unset REM periods. If the mean sleep latency of all five naps is less than IO tin, one speaks of EDS. Severe hypersomnia is defined by a mean latency less than 5 min. Values of over 10 min are considered normal. The capability of the MSLT to measure sleepiness was established by applying the test to a group of healthy volunteers who were deprived of sleep to different degrees. Significant correlations between the severity of deprivation and sleep latency the next day were found. There was, moreover, a significant correlation between subjective sleepiness scores and sleep latencies [WJ]. So the conclusion was drawn that sleep iatencies represented objective quantitative scores of sleepiness. Furthermore, a significant correlation between certain clinical syndromes associated with EDS and MSLT iindings turned out to exist [9,10]. Among others this held for the occurrence of sleep onset REM periods in narcolepsy [3,11,12]. For these reasons it was concluded that the MSLT could be taken as an objective test for the diagnosis of EDS, and for narcolepsy as well. Because of these validated properties, the MSLT has gained widespread acceptance. Grad&y studies were published in which the MSLT was used as an objective
Correspondence to: Dr. G.J. Lammers, Department of Neurology and Clinical Neurophysiology, University Hospital P.O. Box 9600,230O RC Leiden, The Netherlands. Tel.: (71) 262111/262104.
s109 test for the evaluation of the efficacy of some generally accepted drugs [7] and new drugs [13-161 in the treatment of narcolepsy. In none of these studies was a significant improvement of sleep latencies reached. So for all these drugs the conclusion was reached that there was no objective improvement of sleepiness; as a consequence most of these drugs were considered as not useful for the treatment of EDS in narcolepsy. Interestingly an exception was made for dexamphetamine and pemoline because those drugs were already generally accepted as useful on clinical grounds. Moreover, MSLT data of the other generally used drugs seem not to exist [17]. Possibly because of these somewhat disappointing results several new objective tests have been proposed, the only other direct test for sleepiness being the Maintenance of Wakefulness Test (MWT) [7,18]. This test resembles the MSLT, but patients are not asked to sleep but arc in contrast asked to sit down in a chair and to try to stay awake. This test has not yet become generahy accepted, and conflicting results in the assessment of treatment effects have been described [7,19-X]. Even the generally as potent accepted drugs for the treatment of sleepiness in narcolepsy (methylphenidate, pemoline and amphetamine) showed in only one study and not consistent with the used dose a small improvement of sleep latency in the MWT [20]. In addition, more indirect objective tests for the measurement of sleepiness are used: pupillography, event-related potentials, temperature measurement and psychophysiological concentration and reaction time tests, etc. [22-251. Some of these tests were described without a validation of their capability of measuring sleepiness in narcolepsy. In spite of this, if a drug showed an improvement on one of these tests, the conclusion was drawn that such a drug resulted in an objective improvement of sleepiness [20,26]. For this reason one gets the suggestion that finding an improvement of objective sleepiness might in fact be related to parameters of the chosen test rather than to the potency of the drug under investigation. This leads us to a situation where the very drugs, which are considered as the most potent in the treatment of sleepiness in narcolepsy, do in fact not result in an improvement of what is considered the most reliable test for sleepiness. In addition, their effect on the MWT is slight. How can we explain these seemingly contradictory properties of the MSLT (and MWT)? Some explanations of the MSLT’s paradoxical nature have already been considered [7,27]: sleepiness is a combination of several different subjective feelings, of which the MSLT may only measure one; the MSLT is not sensitive enough in narcolepsy; EDS patients suffering of chronic sleepiness are not able to score subjective sleepiness reliably anymore; requiring a patient to fall asleep
may be an inaccurate reflection of the ability of a drug to evoke the exactly opposite effect, i.e. to keep the patient awake. We consider another possibility. Falling asleep does not only involve feeling sleepy, but also changing from the waking to the sleeping state. The ability to change states may differ between healthy and diseased subjects. In fact, an important pathophysiological theory in narcolepsy is based on this: this is called a disturbance of the ‘state boundary control’ [28]. In this theory it is considered impossible for narcoleptic drugs to remain in a certain wake or sleep-stage for protracted periods. Moreover, dissociation of phenomena which normally occur together can be seen, such as the occurrence of muscle atonia in cataplexy; normally, atonia occurs only during REM sleep. As a consequence of disturbed boundary control one may assume that, in narcolepsy, stage transitions occur relatively independent of sleepiness and very short sleep latencies are therefore likely to occur. If for instance a drug does alleviate (subjective) sleepiness substantially, but does not improve the disturbed ‘state boundary control’, then the MSLT-latencies may remain as short as they were before. According to this theory the MSLT can indeed function as an important objective test for the diagnosis of narcolepsy, as it mainly measures ‘state boundary control’ in this disease. But it then is of minor value as an objective quantitative test for sleepiness in narcolepsy, since this is only partly reflected in sleep latencies. Analogous, the MWT does not perform well in the measurement of sleepiness. It, however, is more sensitive to treatment effects on sleepiness, because not only sleepiness and boundary control, as in the MSLT, influence the capability to stay awake. Motivational factors are of influence as well and may be influenced by certain drugs resulting in a second stimulant to keep awake as is measured during this test. Further research must verify this theory of the impact of multiple phenomena on sleep latency and elucidate which component (sleepiness or boundary control) is more important in narcolepsy. In the meantime the problem which test is best suited to measure sleepiness remains unanswered. When MSLT sleep latencies are simply regarded as equal to subjective sleepiness, then a failure of a drug to improve sleep latencies may falsely be taken to mean that the drug does not work. In effect there have been instances where a drug did improve subjective sensation of sleepiness without affecting sleep latencies [7,14,16,21]. Moreover, there is compelling evidence (Lammers, unpublished observation) that the relationship between subjective sleepiness and sleep latencies that exists in healthy subjects changes profoundly in narcoleptic drugs, underlining that the one may not be substituted for the other.
SllO
Conclusion The conclusion seems inescapable that, for the evaluation of treatment effects in narcolepsy, it is better to use subjective sleepiness scores than indirect approximations of sleepiness, which may be objective, but which measure other phenomena as well. After all, this subjective feeling is the complaint of the patient that we, as doctors, are supposed to alleviate. References Aserinsky E, Kleitman N. Science 1953; 118: 273-274. Rechtschaffen A, Kales. Brain Information Selvice/Brain Research Institute, UCLA, 1968. Cat&radon MA, Dement WC, Roth T, Westbrook PR, Keenan S. Sleep 1986; 9: 519-524. Carskadon MA, Dement WC. Sleep Res 19n 6: 200. Calskadon MA, Dement WC. Psychophysiology 1977; 14: 127-133. Carskadon MA, Dement WC. Percept Motif Skills 1979; 48: 495506. Hartse KM, Roth T, Zorick FJ. Sleep 1982; 5: S107S118. Roth T, Roehrs T, Zorick A. Sleep 1982: Sl28-SlW. Roth T, Hartse KM, Zorick F, Conway W. Sleep 1980; 3: 425-439. 10 Richardson GS, Carskadon MA, Flagg W, van den Hoed J, Dement WC, Mitler MM. Electroenceph Clin Neurophysiol 1978; 4.5: 621627.
11 Mitler MM, van den Hoed J, Carskadon MA, et al. Electroenceph Clin Neurophysiol 1979; 46: 479-481. 12 Carskadon MA, Dement WC. Neurosci Behav Rev 1987; 11: 307317. 13 Scrims L, Hartman PG, Johnson FH, Thomas EE, Hiller FC. Sleep 1990; 13: 479-490. 14 Lammets GJ, Arends J, Declerck AC, Kamphuisen HAC, Schouwink G, Troost J. Sleep 1991; 14: 130-132. 15 Boivin DB, Montplaisir J. Neurology 1991; 41: 1267-1269. 16 Guilleminault C, Mancuso J, Salva MAQ, et al. Sleep 1986; 9: 275-279. 17 Lammers GJ, van Dijk JG, Arends J, et al. New Engl J Med 1991; 324: 271. 18 Mitler MM, Gujavarty KS, Browman CP. Electroenceph Clin Neurophysiol 1982; 53: 6.58-661. 19 Mitler MM, Shafor R, Hajdukovich R, Timms RM, Browman CP. Sleep 1986; 9: 260-264. 20 Mitler M, Hajdukovic R, Erman M, Koziol JA. J Clin Neurophysiol 1990; 7: 93-118. 21 Fry JM, Pressman MR, DiPhilippo MA, Forst-Paulus M. Sleep 1986; 9: 269-274. 22 Yoss RE, Moyer NJ, Ogle KN. Neurology 1969; 19: 921-928. 23 Wilkinson R In: Abt L, Reiss B (eds.), Progress in Clinical Psychology. New York: Crune & Stratton, 1968: 2%%3. 24 Pressman MR, Fry JM. Sleep 1989; 12: 239-245. 25 Aguirre M, Broughton RT. Electroenceph Clin Neurophysiol1987: 67: 298-316. 26 Meier-Ewert K, Matsubayashi K, Benter L. Sleep 1985; 8: 95-104. 27 Carskadon MA, Dement WC. Sleep 1982; 5: S67s72. 28 Broughton RJ, Valley V, Aquirre M, Roberts J, Suwalsky W, Dunham W. Sleep 1986; 9: 205-215.
