Improvement of sleep architecture in PD with subthalamic nucleus stimulation

Patients and methods.

Eleven 40- to 60-year-old nondemented patients with severe akinetic idiopathic PD, treated successfully with continuous bilateral high-frequency stimulation of the STN for 3 to 6 months,2 entered the study after giving informed consent. All suffered from chronic insomnia before surgery. Polysomnographic recordings were made, as previously described,3 in two all-night sessions, one with and one without stimulation, separated by a 2-day interval. The order of the session was randomly assigned. Treatment did not vary. All patients took levodopa (mean daily dose, 372 ± 217 mg). Four patients also took dopamine agonists. The last doses were taken at 8 pm. Two patients took benzodiazepines and antidepressants. Polysomnographic recording was continuous from 10:30 pm to 6:30 am, when motor disability was evaluated (Unified PD Rating Scale [UPDRS] III) and levodopa treatment resumed. For sessions without stimulation, the stimulator was turned off at 7 pm. Sleep stages, periodic leg movements (PLM), respiratory events, and arousal were scored as previously described.3 Phasic electromyogram (EMG) activity during REM sleep was defined as the ratio between the duration of REM sleep without atonia and total REM sleep. A neurologist was present during the sessions and examined patients reporting motor disturbances.

Results.

All patients slept during both sessions, except for one who became anxious and asked for the stimulator to be turned on at 1 am and withdrew from the study. Morning UPDRS III scores after a night of stimulation (16 ± 11) were 66% ± 16% lower (p < 0.005, Wilcoxon sign rank test) than after a night without stimulation (49 ± 19). During the control night, six patients reported painful episodes of akinesia and rigidity: five after the first non-REM–REM cycle and one at the end of the night. During the same episode of night akinesia, dystonia was observed in five patients, in the trunk (n = 4), the neck (n = 2), and the legs (n = 3). Seven patients had early-morning foot dystonia. Dystonia appeared each time the patients woke up but was never observed during sleep (figure 1). Akinesia and dystonia coincided with prolonged periods of wakefulness during the control night, but were not observed when the patients were stimulated. During the control night, but not under stimulation, four patients needed to urinate twice. Total sleep time increased during stimulation by 47% (figure 2), and wakefulness after sleep onset was reduced by 51 ± 28 minutes, increasing sleep efficiency (the ratio between total sleep time and total sleep period) by a mean of 36%. Stage 2 sleep increased by 63%. The fragmentation indexes (awakening for more than 15 seconds and arousal for 3 to 15 seconds) and the number of non-REM–REM sleep cycles were similar during both nights (table) . Apnea and hypopnea were rare. Total PLM (indices, 33.2, 52.7, and 12.2) and arousal-associated PLM (indices, 9, 38, and 8) were recorded in three patients during the stimulation night. They were less frequent during the control night (2, 0, and 5, all associated with an arousal). In five patients, phasic EMG activity was observed during 7%, 18%, 27%, 66%, and 10% of REM sleep during the control night, and 15%, 23%, 72%, 100% and 8% of REM sleep under stimulation. The same patients shouted and moved during REM sleep under stimulation but were less agitated without stimulation. According to the patients and their spouses, similar episodes also occurred at home at night, when the patients were continuously stimulated.

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Figure 1. Sleep histograms of Patient 7 without (upper panel) and with (lower panel) stimulation of the subthalamic nucleus. The x-axis shows time, and the y-axis shows sleep stages. Without stimulation (upper panel), cervical dystonia and severe akinesia (first arrow) occurred after the first sleep cycle and was accompanied by a prolonged period of wakefulness. Foot dystonia occurred after the last sleep cycle (second arrow) and was accompanied by an early morning awakening. Nighttime motor disability and dystonia were absent under stimulation (lower panel), and sleep was well organized. Non-REM sleep, open bars; REM sleep, filled bars.

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Figure 2. Total sleep time in minutes of each patient “off” and “on” stimulation.

Discussion.

Suppression of STN stimulation during the night was unpleasant for all patients and may have caused rebound insomnia in predisposed patients. STN stimulation improved nighttime motor disability to the same extent as daytime motor disability reported in other series.2 It also suppressed axial dystonia during the night and early morning dystonia. The reduction of dystonias may be secondary to reduction in medication.4 Because medication was the same during both nights and because dystonias were present only during the control night, STN stimulation may directly improve dystonia.

Whereas total sleep time and Stage 2 sleep increased significantly, the other stages also tended to increase. The duration of wakefulness after sleep onset decreased by almost 1 hour, although the number of awakenings was not altered by STN stimulation. Because stimulation alleviated dystonia but did not alter the sleep–wake pattern, it can be concluded that dystonia followed on awakening but did not cause it. Furthermore, axial dystonia occurred at the end of the first sleep cycle and foot dystonia at the end of the last sleep cycle. Both were followed by prolonged periods of wakefulness. Healthy patients frequently awake transiently between sleep cycles. In patients with PD, if natural arousal at the end of a sleep cycle is followed by painful dystonia and acute akinesia, vigilance may be prolonged; the patients cannot turn over in bed and sleep induction may be impeded.

Periodic leg movements and motor behavior during REM sleep were not alleviated by stimulation at night. PLM are reported in up to one-third of patients with PD and can be alleviated by dopaminergic agents,5 suggesting that they result from altered dopaminergic transmission. The dopaminergic system involved, however, may be distinct from the nigro-striato-pallido-cortical pathway, because STN stimulation does not reproduce the effect of levodopa and dopaminergic agents on the PLM. This conclusion is based on observations in only three patients and must be confirmed. Testing the effect of unilateral STN stimulation on right and left PLM would be of interest to determine whether stimulation triggers contralateral PLM.

Motor behavior during REM sleep is another symptom that was not alleviated by STN stimulation in our patients, although the sample is too small to permit definitive conclusions. Experimental lesions in the locus subcoeruleus cause motor behavior during REM sleep in cats.6 The increased EMG activity during REM sleep could be the result of random variation in the expression of motor behavior during REM sleep. It may be possible that phasic movements during REM sleep would be facilitated like other movements by STN stimulation, whereas they would be restrained by akinesia in the absence of stimulation. The effects of STN stimulation on PLM and motor behavior during REM sleep need further study on larger series of patients.