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January 13, 2004; 62 (1) Articles

Effect of age on MSLT results in patients with narcolepsy–cataplexy

Y. Dauvilliers, A. Gosselin, J. Paquet, J. Touchon, M. Billiard, J. Montplaisir
First published January 12, 2004, DOI: https://doi.org/10.1212/01.WNL.0000101725.34089.1E
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Abstract

Objective: To measure the effect of age on Multiple Sleep Latency Test (MSLT)characteristics, sleep latency, and number of sleep-onset REM periods (SOREMP) in two large populations of narcoleptic patients with similar genetic backgrounds.

Methods: Clinical and polygraphic information on the severity of the condition was obtained on 236 well-defined narcolepsy–cataplexy–human leukocyte antigen DR2–positive patients from Montpellier (France) and on 147 similar patients from Montreal (Canada).

Results: The results show a progressive decrease in the number of SOREMP with age and a progressive increase in the mean sleep latency on the MSLT as a function of age. This finding is also related to the severity of cataplexy as assessed from the clinical history with a progressive decrease in the frequency of cataplexy attacks with age. These results may reflect the progressive increase in sleep latency seen in normal aging and suggest that clinical improvement might be due to changes in the neural mechanisms responsible for SOREMP, which may weaken with age.

Conclusions: The progressive decrease in the number of SOREMP and increase in the mean sleep latency on the MSLT as a function of age suggest that the current criteria used for diagnosis may be too stringent in older patients. The major influence of age on MSLT results should therefore be taken into account when diagnosing a narcoleptic patient.

Narcolepsy is a condition characterized by two major symptoms, namely, excessive daytime sleepiness (EDS) and cataplexy.1–3⇓⇓ Although several methods have been used to assess EDS, the Multiple Sleep Latency Test4 (MSLT) is the most commonly used for positive diagnosis of narcolepsy. A mean sleep latency lower than 5 minutes is considered to be a reliable indicator of pathologic daytime sleepiness. Normal control subjects usually score in a range of 10 to 20 minutes. Scores between 5 and 9 minutes represent a gray area; however, values of sleep latency lower than 7 or 8 minutes are commonly being used to define pathologic sleepiness.5–8⇓⇓⇓ A large survey of narcoleptic patients indicated that 87% had a mean sleep latency on the MLST lower than 5 minutes and 93% lower than 8 minutes.9 In addition to short sleep latencies, MSLT of narcoleptic patients are characterized by the presence of sleep-onset REM periods (SOREMP). In the first report, 100% of narcoleptic subjects had two or more SOREMP, whereas none of the normal control subjects had any SOREMP.10 Further, two or more SOREMP were observed in 84% of narcoleptic subjects, with only 57% of them having a mean sleep latency of <5 minutes.11 These results were recently confirmed by two large studies of narcoleptic patients, with 83 and 74% having at least two SOREMP during the MSLT, 11 and 13% showing one SOREMP, and 6 and 13% having no SOREMP.2,12⇓ In addition, the presence of SOREMP on the MSLT is not specific to narcolepsy. Several other conditions are associated with at least one SOREMP, such as sleep apnea syndrome,2,13⇓ upper airway resistance syndrome,14 periodic leg movements associated with transient arousals,2,8⇓ and normal sleep-deprived subjects.15

There is some evidence that age may influence the MSLT results. Several studies have shown that children with EDS and cataplexy have markedly reduced sleep latency and a high prevalence of SOREMP during the MSLT. In a polygraphic study of 44 prepubertal children with narcolepsy, all children had a mean sleep latency below 5 minutes with a mean of 1.5 minutes ± 39 seconds.16 Twenty-nine children also presented a SOREMP at each one of the MSLT naps, whereas 10 children had four SOREMP and five had three. These results are in contrast with the longer sleep latency and lower rate of SOREMP found in adult narcoleptic subjects.2,7,11,17,18⇓⇓⇓⇓ Furthermore, in a study of 139 normal subjects without EDS, 17% of subjects had more than one SOREMP and 6% had one SOREMP on the MSLT.19 Comparison between subjects with at least two SOREMP on the MSLT and subjects without any revealed that the latter group was significantly older, suggesting that the probability of having SOREMP in normal volunteers also decreases with age.

The aim of the current study was to measure the effect of age on MSLT characteristics, that is, sleep latency and number of SOREMP, in a population of narcoleptic patients diagnosed on the basis of EDS, cataplexy, and the presence of the human leukocyte antigen (HLA) DR2 antigen. We studied narcoleptic populations from Montreal and Montpellier because both populations share a common genetic background, as over 90% of patients in each population have a French origin.3 The main interest of looking at an age effect is to assess the appropriateness of MSLT criteria currently used to diagnose narcolepsy in different age groups.

Patients and methods.

Patients.

We studied 383 unrelated narcoleptic patients (236 men, 147 women): 214 from the Montpellier Sleep Wake Disorder Center (France) and 169 from the Sacré-Coeur Sleep Disorder Center in Montreal (Quebec, Canada). Patients included in this study were recruited between 1986 (date of the generalized use of the MSLT procedure)4 and 2001. The clinical diagnosis of narcolepsy was made by a sleep specialist on the basis of both EDS lasting for >1 year and an unequivocal history of cataplectic attacks, according to the International Classification of Sleep Disorders criteria.20 In addition, all patients were HLA-DR2-DQW1 positive. Patients were divided into five age groups at the time of the evaluation, where Group 1 was under age 21, Group 2 was 21 to 35 years old, Group 3 was 36 to 50 years old, Group 4 was 51 to 65 years old, and Group 5 was older than age 65.

Age at onset of narcolepsy represents the age of occurrence of the first symptoms of narcolepsy, either EDS or cataplexy or both. Other information available in the patient chart was the presence/absence of hypnagogic hallucinations and of sleep paralysis as well as the presence/absence of a positive family history of narcolepsy. In the case of a family of narcoleptic subjects, only the proband was included in the study. Finally, the frequency of cataplectic attacks was assessed on a scale3 from 1 to 5, where 1 represents one or fewer cataplectic attack per year, 2 represents more than one cataplectic attack per year but fewer than one per month, 3 represents one or more attack per month but fewer than one per week, 4 represents one or more attack per week but fewer than one per day, and 5 represents severe cases with at least one cataplectic attack per day. To minimize differences in the interpretation of data obtained from the charts, all the data were pooled by the same investigator (YD).

Methods.

After the first clinic visit, we performed a standard polysomnographic (PSG) recording including one all-night recording in the sleep laboratory followed by an MSLT. The day before the PSG, patients were asked not to drink alcohol or caffeinated beverages and to avoid napping. For the night study, patients went to bed at 11:00 pm and were awakened at 7:00 am. Sleep was recorded and scored according to standard criteria.21 All subjects slept for a minimum of 6 hours during the night preceding the MSLT. The MSLT consisted of five naps scheduled at 2-hour intervals starting at 9:00 am. Patients were invited to lie down in bed in a dark sound- attenuated room and instructed to try to fall asleep. Sleep latency was defined as either three consecutive epochs of stage 1 sleep or one epoch of any other sleep stage. Each latency test was concluded 15 minutes after the onset of sleep or after 20 minutes of wakefulness. A SOREMP was defined as one or more epochs of REM sleep occurring within 15 minutes of the first epoch scored as sleep.

None of the patients had sleep apneas, for example, an apnea index of >5/h, during the all-night PSG recording. None of the patients had any consistent psychiatric or neurologic condition susceptible to produce EDS. All patients were withdrawn from psychostimulant and anticataplectic medications for at least 2 weeks prior to the sleep laboratory investigation. None of the patients was taking any psychotropic medication or other medication known to influence sleep.

Statistical analysis.

To evaluate differences between the two centers and sex differences, t-tests for independent samples for the continuous variables and Pearson χ2 tests for the dichotomous variables were used. One-way analyses of variance (ANOVA) on the number of SOREMP, sleep latency, REM latency, and MSLT were performed to evaluate age differences. Post hoc Tukey highly significant difference (HSD) tests were used to compare means when an ANOVA was significant. Because sleep latency, REM latency, and MSLT data were not normally distributed, the statistical comparisons were made using transformed scores: x = log 10(x + 0.1). Pearson’s correlation coefficients were also calculated to assess the relationship between the severity of cataplexy and age and MSLT findings. To assess the sensitivity of the MSLT findings to diagnose narcolepsy in each of the five age groups, the percentages of patients presenting one or two SOREMP and a mean sleep latency of ≤5, 8, or 10 minutes were calculated.

Results.

The mean age of patients at the time of diagnosis was 42.4 ± 16.9 years (range 5 to 84 years), and the mean age at onset was 22.8 ± 12.2 years. Clinical and PSG data for the two narcoleptic cohorts revealed three main intercenter differences. A higher prevalence of men (69 vs 53%; p = 0.001), a lower prevalence of sleep paralysis (41 vs 52%; p = 0.03), and a milder EDS assessed by the mean sleep latency (4.98 ± 3.1 vs 3.04 ± 2.29; p = 0.0001) were observed in the French group. A gender effect was observed only for the mean sleep latency on the MSLT (p = 0.0007), with a higher daytime sleepiness in women narcoleptic patients than in men.

Table 1 shows the mean sleep latency on the MSLT and the number of SOREMP for each age group. When looking at the entire patient population, the mean sleep latency was 4.12 ± 2.93 minutes and the mean number of SOREMP 3.10 ± 1.46. Two or more SOREMP were observed in 84.2% of narcoleptic subjects, a mean sleep latency of <5 minutes in 73.1%, and both conditions in only 62.9%. Between-group comparisons clearly revealed a progressive decrease in the number of SOREMP with age (F [4,378] = 8.38, p = 0.000002) and a progressive increase in the mean sleep latency on the MSLT as a function of age (F [4,378] = 4.29, p = 0.002) (figure). The progressive decrease in the number of SOREMP with age was observed independently in the French (F [4,209] = 2.9, p = 0.02) and in the Canadian (F [4,164] = 6.57, p = 0.00006) populations. The progressive increase in the mean sleep latency on the MSLT as a function of age was noted in the Canadian population only (F [4,164] = 4.77, p = 0.001) in contrast to the French population (F [4,209] = 1.35, p = 0.25). Tukey HSD post hoc analysis on both populations showed that patients under age 21 had more SOREMP than patients of Groups 4 and 5 (p < 0.05). Patients of Groups 2 and 3 also showed more SOREMP than patients of Group 4 (p < 0.01). More precisely, 65.5% of patients under age 21 had four or five SOREMP in contrast to 34.4% of patients over age 65 (table 2). The mean sleep latency was shorter for patients of Group 1 than for patients of Group 3 (p < 0.01), Group 4 (p < 0.02), and Group 5 (p < 0.01). A mean sleep latency on the MSLT of <5 minutes was observed in 77.6% of patients under age 21 in contrast to 59.4% over age 65 (see table 2). The MSLT criteria currently used to diagnose narcolepsy20 (presence of at least two SOREMP and a sleep latency shorter than 5 minutes) were present in 69% of young narcoleptic subjects but in only 50% of those over age 65 (see table 2).

View this table:

Table 1 Clinical and polysomnographic data of our narcoleptic population divided into five age groups

Figure

Figure. Curves of Multiple Sleep Latency Test (MSLT) (+ SEM) and sleep-onset REM period (SOREMP) distribution for narcoleptic patients.

View this table:

Table 2 MSLT findings for our narcoleptic population divided into five age groups

Sleep paralysis and hypnagogic hallucinations were reported in 45 and 59% of the entire patient population, with 66% of the patients reporting either sleep paralysis or hypnagogic hallucinations and 37% both sleep paralysis and hypnagogic hallucinations. The distribution of sleep paralysis was not similar in the five age groups (ranging from 26 to 57%) (χ2 = 11.86, df = 4, p = 0.02), but between-group differences for hypnagogic hallucinations failed to reach significance (ranging from 48 to 72%) (χ2 = 6.49, df = 4, p = 0.17) (see table 2). The frequency of cataplectic attacks (scale from 1 to 5) for the entire patient population was 3.38 ± 1.22, which corresponds to ≥1 attack per month but <1 per week. The Pearson’s correlation coefficient did reveal a relationship between age and the severity (frequency) of cataplexy (r = −0.10, p = 0.04). However, between-group comparisons did not reveal any difference in the frequency of cataplexy (F [4,372] = 1.55, p = 0.19).

A weak correlation was found between the age at onset of narcolepsy and the mean sleep latency on the MSLT (r = 0.13, p = 0.012). However, the effect of the duration of the disease in the close relationship between MSLT latency and the age was not strong, with only 2% of explained variance. Another correlation was found between severity (frequency) of cataplexy and the number of SOREMP (r = 0.10, p = 0.046), but not with the mean sleep latency on the MSLT (r = −0.08, p = 0.13). There is an inverse correlation between the mean sleep latency and the number of SOREMP on the MSLT (r = −0.32, p = 0.0000001). Finally, a correlation was found between REM latency at night and number of SOREMP (r = −0.26, p = 0.0001) as for sleep latency at night and MSLT latency (r = 0.22, p = 0.0001). However, there was no effect of age on sleep latency at night (F [4,327] = 0.55, p = 0.70) or on REM latency (F [4,327] = 0.17, p = 0.95) (see table 2).

Discussion.

Although there are several indications in the literature that age may influence the outcome of the MSLT, this is the first study in which a large number of patients including children and elderly narcoleptic subjects were studied simultaneously. The main findings of the current study are the significant progressive decrease in the number of SOREMP with age and the progressive increase in the mean sleep latency on the MSLT as a function of age. This finding is also related to the severity of cataplexy as assessed from the clinical history, with a progressive decrease in the frequency of cataplexy attacks with age. However, this change is not as marked as the change in the number of SOREMP. Results of the current study may explain the clinical improvement often seen in narcoleptic individuals with advancing age. There is a common belief that this clinical improvement is due to adaptation to the disease (reduced driving, avoidance of situations triggering cataplexy, etc.) and influenced by treatment. However, there is little literature on the evolution of narcolepsy over time. The EDS tends to persist for the rest of life with either relatively unchanged severity22–24⇓⇓ or only partial diminution in middle age.25 No consistent or clear evolution was found for cataplexy, hypnagogic hallucinations, or sleep paralysis.22,24⇓ In our study, the duration of the disease could not account for all age-related changes in MSLT data. The less symptomatic patients on the MSLT were not significantly diagnosed later. Finally, none of the patients was treated at the time of the recording.

Several studies have clearly shown that narcolepsy may be quite severe in young age.3,16,18⇓⇓ One study looking at the MSLT data of 228 narcoleptic individuals revealed a decrease in total sleep time, sleep efficiency, and stages 3 and 4 and REM sleep across the decades in contrast to an increase in wake time after sleep onset, number of awakenings, and percentage of stage 1, without any difference in EDS and number of SOREMP.26 However, only adult patients (over age 20) with at least two SOREMP and a sleep latency shorter or equal to 6 minutes were included. In addition, the MSLT consisted of only four naps scheduled at 2-hour intervals. This may have masked age differences as patients in this study could only have either two, three, or four SOREMP. Another study failed to observe significant differences in mean age at onset in narcoleptic subjects with fewer than two SOREMP compared with those with two or more SOREMP.2 However, stratification of age groups was not performed, and mean sleep latencies were not studied.

The first question raised by our data is whether the polygraphic criteria20 used currently to diagnose narcolepsy are appropriate, considering the age-related changes in these findings. For example, although criteria such as the presence of two SOREMP and a mean sleep latency shorter than 5 minutes may be present in 69% of young narcoleptic individuals, these two criteria were simultaneously present in only 50% of patients over age 65 (see table 2). Using criteria such as the presence of at least one SOREMP and a mean sleep latency shorter than 8 minutes would only slightly increase the sensitivity of the MSLT in the young population (from 69 to 86%) but would markedly increase this sensitivity in older populations (sensitivity of 84% compared with 50%). However, adhering to rigid MSLT criteria to confirm or refute the diagnosis of narcolepsy may result also in erroneous diagnosis. The change in the MSLT criteria (one SOREMP instead of two and a mean sleep latency of <8 minutes) for elderly narcoleptic subjects will increase the level of falsely positive narcoleptic patients. We thought that MSLT results require interpretation in light of the entire clinical condition.

Results of the current study also raise the question of whether the severity of narcolepsy decreases with advancing age. Results of the MSLT performed in a large number of normal subjects suggest the possibility that the decreased number of SOREMP and the increased mean sleep latency may reflect a normal influence of age on these two physiologic findings.19 A significant number of normal subjects did have SOREMP, and those subjects were found to be younger and sleepier (shorter mean sleep latency on the MSLT) than those without SOREMP.19 As an inverse correlation was found between the mean sleep latency and the number of SOREMP on MSLT in our population, we may imagine that the number of SOREMP may increase with a longer duration of the nap. We could hypothesize that one or more epochs of REM sleep occurring within 20 minutes (and not 15 minutes, as was required)20 of the first epoch scored as sleep may increase the number of SOREMP especially in old narcoleptic individuals. In our study, the decrease in SOREMP was not associated with changes in REM sleep latency at night, a result in contrast with the classic decrease of REM sleep latency during nocturnal recordings in a normal aging population.27 In addition, the decline in nocturnal REM sleep, the lengthening in the duration of the first REM period, and the absence of normal increase of REM sleep in the course of sleep are also frequent with aging.27,28⇓ A marked decrease in nocturnal REM sleep across decades was also reported in narcoleptic subjects.26 This raises the possibility of different REM sleep-triggering mechanisms involved in the SOREMP process and REM sleep latency at night. Our findings suggest that clinical improvement might be due to changes in the neural mechanisms responsible for SOREMP, which may weaken with age.

Aging may progressively decrease the amount of REM sleep and also the overall arousal thresholds. Sleep fragmentation inherent to the normal aging process has been involved in EDS. Indeed, several studies, but not all, revealed an enhanced sleepiness on the MSLT in the elderly.29–31⇓⇓ In narcolepsy, the disrupted sleep and REM sleep at night, which increase with age, were not found to be the causal mechanism for the severe daytime sleepiness.26,32⇓ Rather, an impaired circadian arousal process has been hypothesized to be responsible for EDS in narcolepsy.33,34⇓ In addition, a reduced homeostatic pressure for sleep is well known in older subjects,27 which may also explain the long sleep latencies on MSLT in elderly narcoleptic subjects. The interaction between sleep homeostasis and circadian rhythmicity certainly contributes to the understanding of age-related changes in the timing and quality of sleep and wakefulness states in narcolepsy. Finally, the tendency to display SOREMP varies greatly among narcoleptic subjects, independently of age. We may suppose that genetic factors, including the catechol-O-methyltransferase gene, are also involved.15,35⇓

Acknowledgments

The authors thank Dominique Petit and Alain Besset for expert advice, and Cephalon France for their suppport of this work.

  • Received May 3, 2003.
  • Accepted September 8, 2003.

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