Circadian Variation in Restless Legs Syndrome

One of the defining features of the restless legs syndrome (RLS) is that it shows a notable circadian rhythm with symptoms intensifying later in the day (see Chapter 15). This holds true at least for those who have normal sleep-wake schedules. Those who do shift work, have irregular sleep-wake schedules, or those adjusting to jet lag may not show this pattern. This circadian pattern was noted by Willis in his presumptive case¹ and established as a diagnostic feature by Ekbom.²

However, it was not initially clear that this circadian pattern was due to a specific circadian factor rather than merely reflecting the fact that, later in the day, individuals typically reduce activity and begin to relax. This changed state could itself be the cause of the circadian pattern. In two studies, Trenkwalder, Hening, and colleagues^3,4 showed that there was a true circadian factor to RLS (Fig. 13-1). These investigators used a semiconstant routine study in which hospitalized patients were observed approximately every 3 hours during which they attempted to stay motionless while seated in bed for 1 hour or longer (a modified suggested immobilization test [mSIT]).^5–7 Both subjective (intensity of symptoms) and objective (periodic limb movements [PLM] or motor restlessness) features were measured during 2 days of normal sleep-wake cycles followed by 36 hours of sustained wakefulness. During all days as clock time increased from morning (9:00 A.M.) to early morning the following day (2:00 A.M.), both subjective and objective measures of RLS increased. During continued sleep deprivation, the patients’ discomforts and measures of PLM and motor activity decreased during the day (9:00 A.M. to 3:00 p.m.), before beginning to increase again (6:00 P.M.). Based on these findings, it was concluded that the symptoms and associated motor findings of RLS follow a quite similar circadian pattern with maximum symptoms occurring during the early part of the night.

FIGURE 13-1. Circadian plot. Normalized values of the RLS measures are plotted against clock time from 8:00 A.M. through midnight (24:00) to 8:00 A.M. ACT, activity counts (measure of recorded motor activity); PLMS, periodic limb movements in sleep; PLMW, periodic limb movements when awake; SBJ, subjective leg discomfort measured with visual analog scale. Values were derived from modified suggested immobilization tests when subjects were awake (PLMW, ACT, SBJ) and from sleep recordings during sleep (PLMS). Hours represent beginning of an SIT period or beginning of an hour of enumerating PLMS. Data were obtained from two studies carried out over 72 hours during constant monitoring.^3,4 Hourly averages from the first study³ from 11:00 P.M. to 7:00 A.M. are plotted as a percentage of the maximum (94.9/hr in the period from midnight to 1:00 A.M.). Mean value for 8 subjects and 2-night PSG. Other mV measures are plotted as percent from minimum (0%) to maximum (100%). PLMW is from the first study³; ACT and SBJ are from the second study.⁴ PLMW is minimum of 13.8/hr (9:00 A.M.), maximum of 91.5/hr (2:00). ACT is minimum of 124.9 counts (12:00), maximum of 447.8 (3:00). SBJ is minimum of 2.96 (on 0-to-10 scale averaged over five determinations per 1-hour mSIT) at 9:00 A.M., maximum of 6.04 (at midnight [24:00]). The values of PLMW, ACT, and SBJ were taken by averaging daytime SITs (or mSITs) from the first 2 days of the study; values from hours between 11:00 P.M. and 6:00 A.M. were taken from the third night of total sleep deprivation. There were nine subjects whose measures were averaged in the second study.⁴

The patients in these two studies were also monitored with rectal thermometers to establish the timing of their internal rhythms. The nadir of this rhythm—which occurs at approximately 4:00 A.M. to 7:00 A.M., shortly before waking in most individuals—is denominated as circadian time 0 or phase 0 degrees.⁸ The timing of the temperature minimum in these subjects occurred on average between 4:00 A.M. and 5:00 A.M. in clock time, not notably different from normal subjects of the same age. This made a major deficit in the system that regulates circadian phase unlikely. Comparing the temperature cycle to that of RLS features, it was evident that for these patients, RLS severity was greatest during the falling phase of core temperature, and that around the time of temperature nadir, their RLS began to decrease.

An earlier study had found that PLM, in general, may follow a similar circadian pattern. Most PLM occur during sleep in the first third of the night, whereas later in the night, as the core temperature minimum occurs, the number of PLM may decrease. This pattern is, of course, consistent with RLS but may also be seen in those who do not have the subjective symptoms that would indicate the presence of RLS.

Michaud and colleagues⁹ confirmed the same circadian pattern of RLS severity. They noted—using a similar protocol and repeated episodes of constrained rest—that even normal subjects seemed to show a pattern of discomfort and movement that paralleled that of RLS patients, although to a considerably lesser degree. This observation echoes the finding that pain perception, too, is most intense during nighttime hours.¹⁰ In addition to level of discomfort, the rapidity with which symptoms develop shows the same circadian pattern in RLS patients: when symptoms peak, they develop more rapidly.¹¹

These studies have indicated that RLS does have a true circadian rhythm, and that RLS is most severe before circadian time 0 (core temperature nadir). In addition, there is no evidence to date for an abnormality of circadian timing in RLS and even normal persons may show a similar rhythm of sensory discomfort and motor activity at rest. These findings have led to the questions of how RLS symptoms are related to the circadian mechanism and which features of downstream (circadian output) control are disordered in RLS.

It has been noted that both iron and dopamine (see Chapters 9, 10, and 11), potential mediators of RLS, have a circadian rhythm in which circulating levels are lowest during the evening and night-time hours when RLS symptoms are most intense.

Endocrine Markers of Circadian Phase in Restless Legs Syndrome

Potential abnormalities of circadian function have also been evaluated by means of investigation of the endocrine function across the 24-hour cycle. It is known that the pattern of secretion of many hormones across the day and night follows a circadian pattern.¹² Furthermore, the effects of neuroendocrine secretion on sleep and, conversely, of sleep deprivation on endocrine secretion have also long been established.¹² Thus, it can be expected that the circadian pattern of secretion of certain hormones, particularly of those that are markers of circadian rhythms or are directly influenced by dopaminergic mechanisms, might be altered in RLS. We briefly outline in the following paragraphs the circadian patterns of secretion of several hormones in RLS, both in the untreated and treated conditions as well as after treatment.