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DBS-STN and Sleep: A Review of the Literature

The Parkinson Alliance/DBS-STN Research Team

When sleep is disrupted to the point where ones life is negatively affected to a significant degree, the diagnosis and treatment of a sleep disorder may be warranted. There are many types of sleep disorders (i.e., insomnia, narcolepsy, sleep apnea, etc; APA, 1994), and the causes of sleep disorders are often multi-determined (e.g., medical conditions and symptoms, poor sleep hygiene, psychiatric disorders and stress, medications, alcohol and other substances, etc).

Problems with sleep interfere with many aspects of a persons life and potentially exacerbate co-existing medical and psychiatric conditions. The treatment of sleep problems requires substantial resources; an estimated $16 billion dollars of health care costs are spent annually on the treatment of sleep disorders (NINDS, 2004).

The purpose of this review is to examine the scientific literature on sleep disturbance in Parkinsons disease, with special consideration of sleep in patients who have undergone deep brain stimulation of the subthalamic nucleus (DBS-STN). Sleep disturbances are a significant problem for people with Parkinsons disease (PD). Ones previous experience of sleep at night, as well as during the day, may change in drastic ways as a result of PD. Most commonly, sleep may be disrupted at night due to the movement disturbances caused by PD. PD patients also may experience excessive daytime sleepiness (EDS) at higher rates than healthy individuals. In addition, dopaminergic medications (medications that act like dopamine, a chemical in the brain that, when in low levels, causes PD) are known to cause sleepiness and these medications can cause unintended sleep episodes (irresistible onset of sleepiness; Frucht et al, 1999) and interfere with nighttime sleep.

The effects of sleep problems on persons with PD vary from mild to severe and research shows a clear relationship between poor sleep quality and overall quality of life (Scaravalli et al., 2003). Sleep problems are known to be a risk factor for psychosis in PD and are more common in older PD patients and those with cognitive impairments (Juncos, 1999). Finally, there is some evidence that physicians may under-diagnose sleep disorders in PD patients (Shulman et al., 2002). Tandenberg et al. (1998) conducted one of the largest community-based studies of sleep problems in PD. A sleep questionnaire was administered to 245 PD patients. For comparative purposes, sleep problems in two other groups were surveyed: 100 patients with diabetes and 100 healthy elderly persons. According to the results, nearly two thirds of the PD patients reported sleep disorders. Lower percentages of people reported sleep disorders in the diabetes group (43%) and the healthy elderly group (33%). Tandendberg et al. (1998) found that the most common sleep problems in PD patients were frequent awakening (i.e., fragmented sleep) and early awakening. Importantly, symptoms of depression and duration of levodopa treatment was significantly related to the presence of sleep problems. Even higher estimates of sleep disturbance in PD have been reported. For example, in their review of the diagnosis of PD, Gelb and his colleagues (1999) reported that 96% of PD patients have reported nighttime sleep disturbance. Excessive daytime sleepiness (EDS) is also reported to occur in approximately 40% of patients with PD (Aldrich, 1994). In a more recent article, Rye (2003) reported that unintended daytime sleepiness in PD occurs in approximately 10 to 50% of patients. Although the exact percentages vary, EDS is undoubtedly a problem associated with PD. Ondo and colleagues (2001) examined daytime sleepiness in 303 patients with PD over a 3-month period. They found that daytime sleepiness was more prevalent in men, in more advanced stages of PD, and in those who have had PD for a longer period of time. This study also found that falling asleep while driving was reported by 22.6% of PD patients and this finding was related to increased daytime sleepiness.

Finally, antiparkinsonian medications were also independently associated with daytime sleepiness, but in this group, no single medication was more responsible than the others were. It appears most likely that the amount of the antiparkinsonian medication (i.e., dosage), rather than the type of medication, is the most important determinant of excessive daytime sleepiness (Ramzy et al., 2004). Hobson and colleagues (2002) studied 638 PD patients without dementia. The findings revealed that excessive daytime sleepiness was present in 327 (51%) of the patients. This study also included information about sleep and driving. Of the 420 patients that were driving, 213 (51%) of these patients experienced excessive daytime sleepiness. The type of medication that they were taking made no differences in scores on sleep measures or in the risk of falling asleep while driving. Furthermore, sixteen patients (3.8%) had experienced at least 1 episode of sudden onset of sleep while driving, and in 3 (0.7%), it occurred without warning. The investigators concluded that excessive daytime sleepiness is common even in patients with PD who are independent and do not have dementia. Roth et al. (2003) examined 24 patients who were taking antiparkinsonian medications. Sixteen patients (66%) experienced unintended daytime sleep episodes (irresistible onset of sleepiness) and 8 patients did not experience the irresistible onset of sleepiness, but did report problems with daytime sleepiness. Upon formal examination of sleep in these individuals, overall frequency of pathological (altered sleep caused by PD and/or antiparkinsonian medication) sleepiness was 42% (10 out of 24 patients). Sleep measures, which included a self-report measure, polysomnography (a device used for monitoring and recording brain wave data during sleep), and a clinician rating measure of sleep latency, revealed no significant differences between the groups in total sleep time, sleep efficiency, sleep patterns, or presence of restless legs syndrome or periodic leg movements. There was no relation between degree of nighttime sleep disturbance and level of daytime sleepiness.

These investigators concluded that the unintended, rapid onset of sleep in PD patients occur in those who have excessive daytime sleepiness and are unrelated to the quality and amount of sleep one gets at night. In other words, how much sleep one gets at night does not account for the phenomena of excessive daytime sleepiness, which means that this unintended daytime sleepiness appears to be either part of the disease process for many individuals with PD and/or a side effect of the dopaminergic medication. In addition, excessive daytime sleepiness was also found to be unrelated to specific antiparkinonian medications. The phenomena referred to by some authors as sleep attacks has received special attention in the PD research literature. Sleep attacks were first reported in the late 1990s and were thought to possibly be a direct result of dopamine agonist medication (e.g., pramipexole, ropinirole). Sleep attacks refer to sudden, overwhelming sleep episodes that occur without warning. Survey research suggests that as many as 6% of PD patients experience sleep attacks (Paus et al., 2003). However, controversy exists over whether sleep attacks are truly unpredictable or whether they simply reflect the extreme end of a continuum of excessive daytime sleepiness (EDS). One recent study (Manni et al., 1004) of 24 PD patients used 24-hour continuous polysomnography to examine whether sleep attacks occurred. Indeed, in two patients, brain wave activity consistent with rapid onset of sleep was observed. Additionally, these patients were observed by a caregiver or spouse, who documented that the patient did not appear aware of the sudden onset of sleep. Based on self-report and care-giver questionnaires, symptoms consistent with sleep attacks occurred in 32% of the sample.

Although this study examined only a small number of PD patients, it suggests that sleep attacks do occur in a small minority of patients and that relying solely on questionnaire measures of sleep may overestimate the prevalence of sleep attacks in PD. Clearly, further research is needed to more fully understand the nature and frequency of sleep attacks in PD patients.

The condition rapid eye movement (REM) sleep behavior disorder (RBD) is of special relevance to PD because this disorder is fairly common in PD patients (Lai & Siegel, 2003). The disorder involves uncontrolled and often aggressive behavior (e.g., thrashing legs, punching pillows) during REM sleep that the person is unaware of. Importantly, one recent study (Eisensehr et al., 2001) found that the accurate diagnosis of RBD requires polysomnography (a device that records brain wave data during sleep) and should not rely solely on clinical interview or questionnaire.

Research examining sleep in individuals with Parkinsons disease who have undergone DBS-STN is sparse, but a sufficient number of studies are available for review. These studies have used multiple methods, including polysomnography, clinician ratings, and self-report questionnaires. Monaca and colleagues (2004) studied the sleep/wake cycle before and after DBS-STN in 10 patients. Self-reported sleep quality and sleep recordings using polysomnography were evaluated one month before and three months after initiation of the DBD-STN.

After surgery, the recordings were performed under two conditions: with stimulation (the on condition) and if patients had given their consent in the absence of stimulation (the off condition). With STN stimulation, subjective and objective nighttime sleep qualities were improved. When stimulation was absent, sleep disturbances were similar to those observed before surgery. The investigators concluded that chronic STN stimulation is associated with sleep improvement, which can be explained in part by a decrease in motor disturbances and also by the reduction in dosages of antiparkinsonian medications. They added that one cannot exclude the direct effect of STN stimulation on sleep regulatory centers within the brain. Moreover, the STN stimulation itself may actually impact parts of the brain that are influential in sleep. Iranzo and his co-investigators also evaluated self-reported sleep symptoms and monitored and recorded brain wave data during sleep in DBS-STN patients who had advanced PD. Eleven patients who underwent STN-DBS participated in the study.

Before surgery, seventy-three percent of the patients rated their sleep quality as unsatisfactory. Seven of these had a marked improvement after surgery, and the questionnaires used to evaluate the patients sleep showed significantly improved sleep quality. After surgery, the monitoring and recording of brain wave data during sleep showed an increase in the longest period of uninterrupted sleep and a decrease in the arousal index.

They concluded that in advanced Parkinson's disease, chronic DBS-STN is associated with subjective and objective improvement in sleep quality. These findings were replicated in another recent study of 5 DBS-STN patients (Cicolin et al., 2004) Similar results were found in a study that surveyed 386 non-demented, non-depressed PD patients (Antonini et al., 2004). With regard to night sleep abnormalities, these authors found that chronic DBS-STN improved sleep quality by reducing sleep fragmentation as a result of the reduction of motor disability.

Interestingly, these investigators found that increased daily sleepiness was relatively uncommon in these PD patients, but they purported that this might be associated with stable treatment with high doses of antiparkinsonian medications. In other words, they believe that stable management of high doses of antiparkinsonian medications may help explain why the PD patients in this study did not experience increased daily sleepiness.

Another study, conducted by Hjort and colleagues (2004), examined sleep quality in 2 groups of PD patients. One group consisted of 10 non-demented patients with advanced PD and motor complications who underwent DBS-STN. A control group consisted of 10 patients with advanced PD and motor complications who were on the waiting list for surgery. The PD patients who underwent DBS-STN demonstrated significant improvement of motor function, and their overall rate of quality of sleep was also significantly improved. Moreover, the total score on measure of sleep improved significantly 3 months after surgery compared with the obtained total score on the same measure 1 month before surgery. In contrast, the control group did not show any change in quality of sleep during the four-month interval. Of note, this study found that daytime sleepiness did not change for the PD patients who underwent DBS-STN, suggesting that DBS-STN appears to primarily affect nighttime sleepiness. Another study found some interesting findings with respect to DBS surgery and its effect on nighttime sleep (Arnulf et al., 1998).

The purpose of this study was to evaluate the effects of deep brain stimulation (in multiple brain structures, including the thalamus, globus pallidus, and subthalamic nucleus, which are brain structures deep within the brain) on sleep patterns and night motor signs (e.g., stiffness, muscle contractions, tremor) in patients with PD. Thirteen PD patients were studied, and sleep was recorded by a device used for monitoring and recording brain wave data during sleep (polysomnography). Four patients had unilateral thalamic DBS (DBS of the brain structure called the thalamus only on one side of the brain), 4 bilateral DBS-STN (DBS of the brain structure called the subthalamic nucleus on both sides of the brain), and 5 bilateral pallidal DBS (DBS of the brain structure called the globus pallidus on both sides of the brain). Stimulation was applied continuously one night, and switched off the other night. The results showed that sustained muscle contractions in the foot and neck appeared in the night without DBS (for all groups), always after an awakening, and did not appear in the night with DBS. Stiffness and the inability to move the muscles were improved in the night specifically in those with DBS-STN patients. When present, tremor disappeared at sleep onset with and without DBS. With regard to sleep, total sleep time, sleep efficiency, and REM sleep duration and latencies were not significantly changed between both nights. The authors concluded that DBS improved night motor signs, which can help with sleep, but total sleep time, sleep efficiency, and REM sleep duration and latencies may not necessarily change with DBS. In another study by Arnoff and colleagues (2000), DBS-STN increased total sleep time by 47%, reduced nighttime freezing spells by 60%, and completely suppressed early morning impairment of voluntary movement in a sample of 10 DBS-STN patients. In this study, DBS-STN did not decrease REM-motor behavior symptoms. Finally, Romito et al. (2003) conducted one of the few long-term studies of DBS and found that of the 13 patients examined 3 years after surgery, night sleep improved in all patients and insomnia was resolved for those who suffered from this condition before surgery. In sum, there is no evidence to suggest that DBS-STN worsens sleep problems. The studies conducted to date, although few in number, suggest that sleep in fact improves following DBS-STN. However, well-designed, longitudinal studies are needed to more fully understand the long-term effects of DBS-STN on sleep. Excessive sleep can adversely impact ones quality of life, and it is important to examine what treatments have been implemented to address this issue in PD patients. For example, there have been some interesting considerations as to how to treat excessive sleepiness or unintended episodes of sleepiness (including sudden onset sleep attacks), such as manipulating the dosage of medications as well as adding medications to counteract somnolence. It is well known that in addition to the natural occurrence of sleep disturbance secondary to the progression of PD, antiparkinsonian medications can have somnolence as a side effect. Of interest is the research examining whether some medications used to treat PD are more likely to impact excessive daytime sleepiness than others. For example, Etminan and co-investigators (2001) conducted a meta-analysis (an analysis of several studies) on somnolence with the new medications (the dopamine agonists Pramipexole or Ropinirole) used to treat patients with PD. They found four trials that analyzed patients taking Pramipexole or Ropinirole as compared with those taking placebo. In addition, they found seven trials that analyzed patients taking Levodopa and Pramipexole or Ropinirole as compared with those taking Levodopa alone. These investigators concluded that patients with PD using Pramipexole or Ropinirole are at higher risk of experiencing somnolence relative to patients taking placebo. Similarly, patients taking Levodopa plus either one of these dopamine agonists are at higher risk than those taking Levodopa alone. In a more recent study, Halloway and colleagues (2004) examined the effects of Levodopa and Pramipexole on PD patients, and they found that somnolence was more common in Pramipexole-treated participants than in Levodopa-treated subjects. In contrast, other studies have stated that total dopaminergic drug dose (the amount of the medication) rather than the specific medications used is the best predictor of daytime sleepiness in PD patients receiving dopamine agonist therapy (Ondo et al., 2001; Razmy et al, 2004; Roth et al., 2003). Thus, one form of treatment would include having increased knowledge of and management of medications that induce episodes of sleep. Furthermore, a physician may make an attempt to reduce the medications that have the side effect of sleepiness, but, consequently, movement disturbances may get worse. As a result, stimulant medications (medications that promote wakefulness and alertness) have been prescribed to help increase wakefulness. Rye (2003) indicated that sleepiness in PD, especially a narcolepsy-like problem, might necessitate treatment with stimulant medications. However, the type of stimulant needs to be carefully considered. Stimulants, such as amphetamines (e.g., Ritalin, Pemoline), which are commonly used in narcolepsy, can have significant side effects and are drugs of potential abuse. Nieves and Lang (2002) have found that Modafinil, which is also a type of stimulant, can be very effective in controlling excessive daytime sleepiness that is caused by dopaminergic medications in PD. Additionally, they found that Modafinil did not adversely affect PD motor function and may even permit the use of higher doses of dopaminergic drugs in patients intolerant of these as a result of somnolence. In sum, empirically validated treatment for daytime sleepiness has been limited to use of medications, such as using awake-promoting medications.

Although some medications have been found to be effective in helping to increase alertness and arousal, it is very important to discuss with a physician whether or not stimulant medications are appropriate and, as important, which types of stimulants are recommended. In conclusion, sleep disturbances appear to be a common experience for individuals with PD. Moreover, research has found that both daytime sleepiness and nighttime sleepiness are disturbances that might occur for these individuals. Overall, research indicates that there is a positive effect on sleep disturbance after undergoing DBS-STN as a treatment for PD. Specifically, DBS-STN has been found to have a significant impact on the quality of nighttime sleep, as this surgical procedure minimizes, if not eliminates, fragmented sleep that previously resulted from motor disturbances.

The beneficial effects of DBS-STN on sleep are encouraging for substantial reasons. First, improving sleep is likely intimately linked to improving quality of life and decreasing emotional distress (e.g., depression, anxiety). Second, the typical reduction of antiparkinsonian medication following DBS-STN may beneficially affect sleep hygiene by decreasing daytime sleepiness, which is a common side effect of many medications. Of note, up to this date, although research clearly delineated benefits of DBS-STN on nighttime sleep, further investigation needs to be conducted to discern to what extent DBS-STN helps daytime sleepiness. Furthermore, it is important to discuss with your treating physicians what types of medications may cause sleepiness and if there are any medications that might be appropriate to treat somnolence, such as stimulants. In sum, the decrease in or elimination of sleep disturbances observed after one receives DBS-STN could play an important role in improving quality of life in individuals with PD.

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