Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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The significant impact of Parkinson disease on sleep was clearly noted in James Parkinson’s remarkable description of the illness in his 1817 monograph, “An Essay on the Shaking Palsy.” He correctly noted that the motoric symptoms of Parkinson disease, such as severe nocturnal emergent tremor or nocturnal immobility, have great potential to interrupt sleep. Today, we are aware that the sleep-Parkinson disease interaction takes many other forms, including the effect of Parkinson drugs or Parkinson-associated behavioral symptoms (depression and psychosis) on sleep, and the (mostly beneficial) effect of sleep on the symptoms of the disease. The authors highlight the common sleep disorders found in Parkinson disease, looking at both the potential etiologies and treatment options. One of the most striking sleep problems in Parkinson disease is excessive daytime sleepiness, which is in part due to medication side effects, but also highly correlated with age and duration of disease. We have also learned that many sleep disorders that are moderately common in the general population, such as restless legs syndrome and REM sleep behavior disorder, could be more prevalent among Parkinson patients, the latter condition sometimes antedating clinical Parkinson disease by years. Finally, this update discusses the role of circadian disruption in the development of Parkinson disease, an exciting new area of research and potential intervention.
• REM sleep behavior disorder is 1 of the most common sleep disorders associated with Parkinson disease and sometimes antedates the motoric features of Parkinson disease by years.
• Daytime sleepiness and fatigue are common complaints in Parkinson disease patients, especially in the elderly and in men.
• Circadian dysfunction is an important emerging component of sleep dysfunction in Parkinson disease, with recent demonstration of changes in melatonin release patterns and potential benefits seen from timed bright light exposure.
• The common notion that parkinsonian tremor disappears entirely during sleep is not completely true as tremor can re-emerge, sometimes significantly, during sleep arousals.
• Bedtime dosages of dopaminergic medications, especially long-acting preparations, are very useful to combat nocturnal re-emergent parkinsonian symptoms, such as high-amplitude tremor or severe akinesia, while in bed, which can significantly disrupt sleep.
In 1817 James Parkinson, a medical practitioner from the township of Shoreditch, published his remarkable monograph entitled “An Essay on the Shaking Palsy.” In this monograph he described 6 patients he had observed with a unique neurologic disorder that would later come to bear his name. In the first 6 lines of this monograph, he confirmed the prominent clinical features of this condition much as we know them today:
. . . involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported. . . with a propensity to bend the trunk forwards, and to pass from a walking to a running pace. . . the senses and intellects being uninjured.
In addition to its classical features, Parkinson was also well aware of the syndrome’s interaction with sleep. On page 7 of his 63-page monograph he noted, “The tremulous motion of the limbs occurs during sleep, and augment until they awaken the patient and frequently with much agitation and alarm.” Commenting on the potential severity of tremor in advanced Parkinson patients, Parkinson goes on to state, “but even when exhausted nature seizes a small portion of sleep, the motion becomes so violent as not only to shake the bed-hangings, but even the floor and sashes of the room” (74). Parkinson’s vivid and concise descriptions of this syndrome and its accompaniments remain among the most remarkable and venerated accomplishments in clinical neurology. Although he coined the Latinized term “paralysis agitans” in place of shaking palsy, both terms have gradually disappeared in favor of Parkinson disease, the title that honors the master clinician. Today, even those conditions that clinically resemble Parkinson disease, although they are histologically different, are referred to collectively as the Parkinson syndromes.
Deterioration of sleep quality and duration are considered as markers of the prodromal phase of parkinsonism (55). Sleep abnormalities are common nonmotor symptoms of Parkinson disease, interesting as many as 93% of Parkinson disease patients. In a cross-sectional study on 157 Parkinson disease patients using an actigraph for 6 consecutive nights, a significant difference in objective sleep quality and quantity between Parkinson disease patients and controls has been found (47).
Altered NREM sleep microstructure is present even at an early stage of Parkinson disease, suggesting an early alteration of the central pathways involved in NREM sleep building-up and stability (79).
More importantly, it was demonstrated that poor sleep quality in patients with Parkinson disease correlates with impaired cognition (80; 56), pain scores (66), and the presence of comorbid sleep disorders is predictive of increased nonmotor symptoms (65). In contrast, a good sleep quality characterized by deeper slow wave sleep might relate to a more benign course of Parkinson disease (95). However, it is often difficult to ascertain whether the reported sleep disturbances are related to Parkinson disease itself or to the antiparkinsonian drugs. For example, it may be difficult to determine whether sleep disruption unrelated to Parkinson medications is caused by nocturnal reemergence of akinesia, rigidity or tremor, associated parasomnias, disruption of the circadian rhythm, or a primary alteration of sleep architecture. A polysomnographic study on 23 drug-naïve Parkinson disease patients showed a reduced sleep efficiency, longer sleep latency, and reduced duration of stage 3 NREM and rapid eye movement sleep compared to controls (36). Twelve patients were subsequently evaluated after 2 months of levodopa therapy with a significant improvement of sleep efficiency and reduction of sleep latency and wake-after-sleep-onset (36). Another polysomnographic study performed on 30 early-stage Parkinson disease patients (80% under dopaminergic therapy) revealed that about half of the patients reported sleep complaints and demonstrated a significant increased sleep latency, reduced sleep efficiency, and rapid eye movement sleep percentage compared to controls (14).
Most of the mechanisms by which Parkinson disease can affect sleep become more prominent as the illness progresses, explaining why studies of mild Parkinson disease patients may not uncover the full spectrum of sleep disturbances (120). In an Italian cohort study looking at 1072 patients with Parkinson disease, fatigue was the most common symptom (58%), followed by insomnia (37%), which was often confounded by nocturia (35%). REM sleep behavior disorder (30%), excessive daytime sleepiness (21%), and restless legs syndrome (15%) were also frequent complaints (10). Two multicenter cross-sectional studies demonstrated that more than half of the patients complained of distressful fatigue (103; 129) whereas nocturia was present in 55% of treated patients (129).
Insomnia and Parkinson disease. Insomnia in Parkinson disease is multifactorial, with multiple components of the underlying disease process and treatment modalities contributing to difficulty falling asleep and maintaining sleep. Nonmotor symptoms (fatigue, depressed mood, and autonomic problems) are closely associated with reported insomnia. Anxiety and depression may constitute a risk factor for insomnia in Parkinson disease. The relationship between insomnia and anxiety is bidirectional, suggesting that both anxiety and sleep disorders can start a negative spiral in Parkinson disease patients, where 1 enhances the other (91).
Parkinson disease patients suffer from increased sleep latency and an increased frequency of nocturnal arousals. These frequent arousals may stem in part from abnormalities in sleep architecture that are present in Parkinson disease, including a reduction in total slow-wave and REM sleep and a decrease in sleep spindle density. The reduction in slow-wave sleep in Parkinson patients correlates with age and duration of disease, but not with the administration of daytime dopaminergic medications.
Each of the fundamental motor signs of Parkinson disease: tremor, rigidity, and bradykinesia, can also contribute to sleep fragmentation and result in complaints such as immobility in bed and pain related to nocturnal rigidity. The exact sequence of events that leads to awakening in patients with these nocturnal motoric symptoms is less clear. Tremor, once thought to disappear entirely in sleep, is now known to be 1 of the causes of arousals in Parkinson disease patients. Polysomnographic studies have shown that tremor usually appears in stage 1 or 2 of NREM sleep, after arousals, and during sleep stage transitions, in an attenuated form. This attenuated tremor may not result in awakening, but after a true awakening, no matter the cause, more severe tremor can appear and can be associated with sleep disturbance. Severe tremor may also prevent patients from initiating sleep at bedtime, as noted in James Parkinson’s original monograph. Other forms of abnormal motor activity can appear during sleep, including rapid eye blinking at the onset of sleep, blepharospasm, and non-REM sleep-associated tonic contraction of limb extensors and flexors.
Bradykinesia can also contribute to sleep disturbance (12). In some patients with advanced disease, the effect of dopaminergic medication can wear off as the night progresses. The severe immobility that results from this will cause sleep disturbances in those patients.
Nocturnal immobility is a significant complaint in Parkinson disease patients. Parkinson disease patients sleep more frequently in a supine position than controls and the supine position is associated with a higher apnea-hypopnea index end excessive daytime sleepiness (102). Moreover, it was demonstrated that patients with nocturnal immobility reported significantly worse subjective sleep quality and objectively had significantly lower sleep efficiency. Seventy-nine percent of Parkinson disease patients indicated the need to void at night, yet 35% were unable to get out of bed unaided (112). The third fundamental symptom of Parkinson disease, rigidity, may appear during an awakening, resulting in pain that prevents the resumption of sleep.
The potential for re-emergent parkinsonian symptoms to disrupt sleep suggests that nighttime dosages of antiparkinsonian medications might improve sleep (36). There is some controversy, however, about whether a bedtime dose of levodopa or a dopamine agonist improves sleep in Parkinson disease. Clinical experience suggests that in many moderately severe to advanced Parkinson disease patients, nocturnal amelioration of significant motor signs is often an important step in attempting to normalize sleep. This can be accomplished by around-the-clock dosing with antiparkinsonian medications, or more simply, with administration of a bedtime dose of sustained release carbidopa-levodopa (116), a sustained-release dopamine agonist (85), or the transdermal dopamine agonist, rotigotine (108). It has been proven that the rotigotine patch is well tolerated and safe (32). Rotigotine reduces nocturnal motor activity, duration of wake episodes after sleep onset (WASO), nocturia, pain, and coexisting sleep disorders such as restless legs syndrome; it may also reduce the number and duration of daytime sleep episodes in Parkinson disease patients (16; 77). There is also the possibility that antiparkinsonian drugs can alter sleep. Because of its potentially alerting amphetamine metabolites, the MAO-B inhibiting agent selegiline can result in insomnia (64). However, rasagiline does not have amphetamine metabolites and may have a lower potential to cause or exacerbate insomnia. Rasagiline administration significantly reduces the mean sleep latency and increases the mean total sleep time (64; 93). Levodopa has the potential to alter sleep architecture, especially in the months immediately after the initiation of therapy. In some patients, dopaminergic drugs administered at high dosages late in the evening can increase sleep latency and result in sleep fragmentation (99). Accordingly, unless a late evening dosage of levodopa or dopamine agonist is required to control nocturnal motor symptoms, it should be eliminated or distanced from bedtime.
A variety of behavioral side effects that might adversely affect sleep can result from antiparkinsonian therapy, including memory loss, confusion, paranoia, psychosis, hallucinations, and vivid dreaming. Among these adverse effects, nocturnal hallucinations and vivid dreaming have the greatest potential to interrupt sleep. With chronic dopaminergic therapy, some patients report that dreams become increasingly vivid even though dream content remains relatively unchanged. Medication-induced vivid dreams not only have the potential to interrupt sleep, but they have been thought to be a premonitory sign of hallucinations and advanced psychosis, suggesting the need for treatment. The initial event in this behavioral cascade leading from vivid dreaming to overt hallucinations may be a reduction in REM sleep related to levodopa therapy. This progression is most likely to occur in Parkinson disease patients who are aged, cognitively impaired, and already have disturbed nocturnal sleep of any cause. Prospective studies of this sequence of events have questioned the predictive significance of vivid dreams, but, despite this controversy, it still seems advisable to reduce the bedtime dosage of antiparkinsonian drugs and distance it from bedtime, if possible, when vivid dreams appear. Although levodopa and the dopamine agonists are the most common triggers, anticholinergic drugs, selegiline, and amantadine can also produce this syndrome. Their intake should be reduced first before attempting to taper more clinically effective primary dopaminergic agents.
Dyskinesias are abnormal involuntary movements resulting from dopaminergic therapy that are usually choreiform or dystonic in nature. Typically, choreiform dyskinesias occur when a dopaminergic drug is manifesting its greatest central effect (peak dose dyskinesia), or less commonly, at the beginning and end of the central effect (biphasic dyskinesia). Choreiform dyskinesias, irrespective of their temporal pattern of occurrence, tend not to persist or emerge during sleep and are seldom the cause of self-reported sleep disturbance. Dystonic dyskinesias, on the other hand, are more likely to impact sleep. Although dystonia can also occur in untreated Parkinson disease patients, it is more commonly related to the administration of dopaminergic medications. Dystonic dyskinesias can occur with the peak effect of dopaminergic agents or in a biphasic pattern but even more commonly appear at the end of an interdose period when the central effects of medication have nearly or totally worn off (ie, on awakening in the morning after a night-long, medication-free interval). During this pattern of occurrence, referred to as early morning dystonia, painful plantar flexion of the feet and curling of the toes is typical. Less commonly, facial and upper extremity musculature are also affected.
Levodopa-induced myoclonus occurs predominantly, but not exclusively, at night. It typically involves axial and proximal muscles and can appear during non-REM sleep as often as 30 times per night. These movements usually emerge only after chronic administration of levodopa. It is not always clear whether they interrupt the sleep of the Parkinson disease patient, but they can pose a problem for the bed partner.
Akathisia, an irresistible internal desire to move, is seen in some Parkinson disease patients receiving levodopa and, rarely, in the untreated patient. It can be distinguished from restless legs syndrome by its lack of relationship to recumbency, the absence of associated sensory phenomena, and the involvement of the entire body. Although not completely confined to bedtime, it is commonly nocturnal in Parkinson disease patients. Akathisia has a variable relationship to the timing of levodopa administration and can occur in either the "on" or "off" state. Accordingly, in treating Parkinson disease patients with severe nocturnal akathisia it is sometimes necessary to experiment by first increasing and then decreasing the evening dosage of dopaminergic medication. Should both approaches fail, a bedtime dosage of the atypical neuroleptic clozapine may be effective in treating this symptom.
Excessive daytime sleepiness and Parkinson disease. Excessive daytime sleepiness is common in Parkinson disease and is probably multifactorial (75; 70; 128), occurring independently of nocturnal sleep disturbances (51). Several risk factors for excessive daytime sleepiness in Parkinson disease have been demonstrated, such as male gender, poorer nighttime sleep quality, cognitive impairment, the presence of hallucinations, dysautonomia, and the dose of dopamine agonists (128). Longitudinally, excessive daytime sleepiness in Parkinson disease has been associated with nontremor dominant phenotype and the presence of autonomic dysfunction, depression, anxiety, and probable REM sleep behavior disorder, but not cognitive dysfunction or motor severity (02). To date, conflicting results regarding the higher prevalence of excessive daytime sleepiness in de novo Parkinson disease patients are present. A study on 159 drug-naïve patients found a higher prevalence of excessive daytime sleepiness in Parkinson disease compared to healthy controls at disease onset as well as during follow-up, and it was associated with male gender, depression, and higher activities of daily living scores on the Unified Parkinson's Disease Rating Scale (UPDRS) (106). On the contrary, a case-control study on a large cohort of Parkinson disease patients demonstrated that the prevalence of daytime sleepiness in de novo patients was not dissimilar to that of healthy controls (98). A metaanalysis showed that approximately one third of patients with Parkinson disease had excessive daytime sleepiness, which may be associated with the severity of the disease, depression, and male sex, or a combination of neurodegeneration and medication (98; 33). Fatigue appears to be a separate symptom in Parkinson patients that is unrelated to daytime sleepiness or nighttime sleep dysfunction and is found in up to one third of patients with Parkinson disease (103).
Sleep-disordered breathing. A review of case-control polysomnographic studies on Parkinson disease patients highlighted the lack of consistency of the data regarding this topic (75; 70; 104). Significant respiratory dysfunction is not seen in mild Parkinson disease. A polysomnographic study of Parkinson disease patients of all severities revealed a similar incidence of obstructive sleep apnea (OSA) in Parkinson disease and controls (109). If present, obstructive sleep apnea is associated with sleepiness, cognitive dysfunction, and higher baseline MDS-UPDRS scores (61; 60).
Obstructive sleep apnea severity is lower in Parkinson disease patients with REM sleep behavior disorder and with higher levodopa equivalent dose (96).
Obstructive sleep apnea is much more common in multiple system atrophy than in idiopathic Parkinson disease, and stridor is not seen in the latter condition.
Medications and excessive daytime sleepiness. Most of the commonly used antiparkinson medications, including levodopa, amantadine, dopamine agonists, COMT inhibitors, and anticholinergic agents have some potential to induce excessive daytime somnolence. Selegiline, on the other hand, is virtually never associated with excessive daytime sleepiness. Among the antiparkinson drugs, levodopa and dopamine agonists are the most common cause of medication-related somnolence. Typically, patients complain of an irresistible desire to sleep within 30 minutes of a dosage of standard or sustained release carbidopa-levodopa. Polysomnographic studies in such patients have demonstrated diurnal NREM sleep episodes after 30 to 60 minutes of a dosage of levodopa (25). Multiple sleep latency tests in these patients have been normal, whereas visual reaction times worsened after 30 and 60 minutes after levodopa intake (25). The pathogenesis of this phenomenon is unclear. Some excessive daytime somnolence in Parkinson disease undoubtedly occurs independent of medications, reflecting microstructural changes in the sleep-related circuits (07), but the striking temporal relationship between somnolence and the administration of the last dosage of medication in some patients suggests that, at least in these circumstances, a true cause-effect relationship exists. Unlike somnolence, fatigue does not appear to be related to therapy with dopamine agonists or levodopa (73), but it is said to be the single most common reason cited for medical disability insurance claims.
A potentially dangerous form of somnolence leading to serious motor vehicle accidents has been reported in patients being treated with dopamine agonists (35). Eight Parkinson disease patients taking pramipexole and 1 receiving ropinirole fell asleep while driving. Similar episodes have also been described in patients being treated with the dopamine agonists bromocriptine, pergolide, and lisuride. Because of the suddenness of sleep onset in some cases, these episodes are sometimes labeled "sleep attacks." A metaanalysis of 20 publications reporting similar episodes in parkinsonian patients concluded that the attacks are a class effect for a variety of dopaminergic medications, but they have been most commonly reported in patients receiving dopamine agonists such as pramipexole or ropinirole (41). It was demonstrated using a maintenance of wakefulness test that increased use of dopamine agonists was associated with decreased alertness; however, increased levodopa doses actually were associated with higher levels of alertness (13). Ambulatory polysomnography in Parkinson disease patients has confirmed that patients experiencing sleep attacks do have a higher degree of daytime somnolence, in that they have higher Epworth Sleepiness Scale scores and a higher proportion of microsleeps and intentional naps (57). A sleep scale specific to Parkinson disease was introduced (19) and has been found to be useful in identifying a variety of sleep disturbances, including excessive daytime sleepiness. Sleep attacks can be improved by reducing or discontinuing the offending dopamine agonist, if medically feasible, but when this strategy is not possible, another useful approach is to change to a controlled-release agonist preparation because these agents may be less likely to induce sudden sleep.
Mood disorders and sleep in Parkinson disease. The behavioral manifestations of Parkinson disease can also impact sleep. Depression or anxiety symptoms are significantly associated with poor sleep quality in Parkinson disease (18). Depression occurs in over 40% of Parkinson disease patients, and these individuals have a higher incidence of sleep complaints than those who are not depressed. The typical clinical and polygraphically defined sleep changes caused by depression (including shortened REM sleep latency, increased number of arousals, and early awakening) occur more frequently in depressed than nondepressed Parkinson disease patients. The relative contributions of depression to disturbed sleep can be difficult to separate from the other effects of Parkinson disease. Some studies have suggested that within this population, age, illness-related variables and levodopa dose are more strongly correlated with sleep disturbance than the degree of depression. Others have found that depression correlates with sleep disturbance more than any motor or demographic variable of Parkinson disease. Dementia, another common behavioral manifestation of Parkinson disease, can indirectly impact sleep. Cognitively impaired Parkinson disease patients are much more susceptible to nocturnal confusion and hallucinations.
Circadian rhythms and Parkinson disease. Disruption of normal circadian rhythms is another potential effect of Parkinson disease on sleep (70; 115). Reversal of the sleep cycle is common in Parkinson disease, especially in elderly patients with advanced disease. Typically, affected patients nap frequently during the day and are awake at night. This circadian abnormality is multifactorial in origin. Many of the standard external markers of diurnal rhythmicity, such as mealtime and scheduled activities, are altered by Parkinson disease and the timing of medications used to treat the condition. Often, a natural circadian pattern of worsening and improvement in dopamine-dependent functions may dictate certain periods of the waking day when the patient is ambulatory and active (typically the early morning) and other times when there is relative immobility and a tendency to nap (typically late afternoon).
In addition, it is possible that there is intrinsic pathology contributing to this dysfunction, with the primary circadian pacemaker and the suprachiasmatic nucleus being directly affected by the disease. It has been demonstrated that melatonin, a biological marker of the circadian system, shows decreased amplitude in Parkinson disease patients compared to controls (14), with the greatest differences seen in patients with Parkinson disease and excessive daytime sleepiness (114). In addition, the presence of alterations in body core temperature profile, another circadian marker, in Parkinson disease patients is still controversial (76; 127). Finally, studies have demonstrated that bright light therapy, often used to reset the circadian clock, can improve motor symptoms in Parkinson disease and subjective sleep quality (90); however, the appropriate timing and duration of light are still being determined. A deeper understanding of the dysfunctions of the networks governing circadian rhythms will provide not only a greater understanding of Parkinson disease neuropathology but will also hold the promise for effective therapies (37).
Parasomnias. Parkinson disease patients experience abnormal motor activity and behaviors (parasomnias) during sleep, with the most common being REM sleep behavior disorder (69; 124; 06). Little is known about the time course of REM sleep behavior disorder in Parkinson disease. In a prospective study on moderate-to-advanced Parkinson disease patients, despite the subjective improvement of REM sleep behavior disorder symptoms in one-fourth of patients, REM sleep without atonia (RSWA) increased significantly at 3-years follow-up, correlating with the clinical evolution of motor and nonmotor symptoms (38). In another study, REM sleep without atonia is associated with an increased and more symmetric presentation of upper limb rigidity in mild to moderate Parkinson disease (53). One study underlines a significant association between doses of levodopa and REM sleep behavior disorder symptoms in Parkinson disease patients (59).
Several reports have strengthened the notion that patients presenting with REM sleep behavior disorder often develop Parkinson disease later in life. A multicenter longitudinal study assessed the risk of developing a synucleinopathy in a cohort of 279 patients with idiopathic REM sleep behavior disorder, finding a relative risk of 25% after 3 years and 41% after 5-years follow-up (78). Overall, REM sleep behavior disorder is a promising target for neuroprotective trials in the future, prompting a consensus statement for devising studies of neuroprotection against Parkinson disease (92).
In addition, a controlled study conducted on 113 Parkinson disease patients demonstrated that REM sleep behavior disorder increases with disease duration, and it may be preceded by prodromal REM sleep behavioral events (100). The appearance of REM sleep behavior disorder in currently diagnosed Parkinson disease patients is associated with a high risk of developing visual hallucinations, dementia (28), impulse control disorders (17), and functional dependency (49), with a worse prognosis (34). Comparing 25 Parkinson disease patients with REM sleep behavior disorder and 25 Parkinson disease patients without REM sleep behavior disorder, patients with REM sleep behavior disorder had significant impairment in mini mental state examination category fluency test (FAS test), frontal assessment battery, attention (digit span backwards, Corsi span), verbal memory (story recall), and Rey's auditory verbal learning test (44). REM sleep behavior disorder in Parkinson disease is also associated with isolated apathy and increased severity of depressive symptoms (09).
Although REM sleep parasomnias have been extensively described in Parkinson disease, little is known about NREM parasomnias in Parkinson disease. A questionnaire study on 661 Parkinson disease patients showed a sleepwalking occurrence of 1.8 % and a night terrors occurrence of 3.9 % (122).
Periodic limb movements of sleep and restless legs syndrome. Periodic limb movements of sleep can be seen in up to 58% of Parkinson disease patients and they increase with increasing disease severity (99). Periodic limb movements of sleep consist of stereotypic movements of the lower extremities characterized by extension of the great toe as well as ankle and flexion at the knee and sometimes the hip. Rarely, the upper extremities are involved. SPECT of the dopamine transporter has suggested that periodic limb movements of sleep frequency in Parkinson disease correlates with striatal dopaminergic dysfunction.
Although the relationship between restless legs syndrome and Parkinson disease is still under debate and the pathophysiological link is still unclear, the association between these 2 disorders is common (83). As compared to nonparkinsonian patients, patients with Parkinson disease have been found to have onset of restless legs syndrome at an older age and they are less likely to have a family history of the syndrome (83; 119). Furthermore, the syndrome has been associated with lower ferritin levels also in patients with Parkinson disease. A longitudinal study has demonstrated that restless legs syndrome is present in drug-naïve Parkinson disease patients at the time of the first diagnosis (4.6%) and that its prevalence increases during follow-up (6.5% at 2 years; 16.3% at 4 years) (63). Restless legs syndrome prevalence was higher in female (13%) than in male Parkinson disease patients (11%) and among patients who had previously received Parkinson disease treatment (15%) than among drug-naïve patients (11%) (121). Parkinson disease patients with restless legs syndrome suffer from worse life and sleep quality, depression, anxiety, and autonomic disturbances (123).
Effect of sleep on Parkinson disease. Sleep typically has a salutary effect on the symptoms of Parkinson disease. The most common diurnal pattern of symptom severity in Parkinson disease is that of improvement of akinesia and rigidity in the morning just after arising paralleled by improvement in nonmotor dopamine-dependent functions at the same time. In a questionnaire-based study, 6.9% of Parkinson disease patients reported improvement in symptoms following nocturnal sleep (111). Sleep benefit was more common in patients with longer disease duration, with shorter total sleep time and longer sleep latency (97). Better objective sleep measures were significantly associated with shorter low morning mobility (48). The beneficial effect of sleep on the symptoms of Parkinson disease can be so prominent in some patients as to eliminate the need for antiparkinsonian medications for the first half of the day. The mechanisms underlying this phenomenon are not yet fully understood. In addition to the salutary effect of sleep on the motor signs of Parkinson disease, there is additional evidence that lack of quality sleep is associated with impaired executive function, but not memory, in apparently non-demented Parkinson disease patients.
A 57-year-old man with a 2-year history of Parkinson disease was initially treated with pramipexole in a dosage of 1 mg 3 times daily with good relief of his symptoms of asymmetric upper extremity tremor, mild generalized bradykinesia, and moderate rigidity of both arms and both legs. His wife complained that he frequently shouted out at night and grabbed her arm as though wrestling with her while he was still asleep. A clinical diagnosis of Parkinson disease-associated REM sleep behavior disorder was made and the patient was treated with clonazepam 0.5 mg at bedtime. This resulted in total resolution of these nocturnal episodes. Over the next 5 years, the motor symptoms of Parkinson disease progressed, requiring the addition of sustained-release carbidopa or levodopa, which he took in dosage of 50/200 at 8:00 AM, 12:00 PM, 6:00 PM, and 11:00 PM (bedtime). He soon began to develop vivid dreams and nocturnal hallucinations. Accordingly, his bedtime dosage of carbidopa-levodopa was discontinued, resulting in resolution of the nocturnal hallucinations. Without this bedtime dosage, he became severely immobile at night and was unable to shift position or arise to void despite a full bladder. He was restarted on a smaller dosage of sustained-release levodopa at bedtime, in addition to a bedtime dosage of 50 mg quetiapine. On this regime he was less akinetic during the night, yet he did not suffer from nocturnal hallucinosis.
The sleep disturbances experienced by Parkinson disease patients are multifactorial. It is known that Parkinson disease can affect sleep through disruption of micro- and macro-sleep architecture (70; 79). Whole-night video polysomnography-high-density EEG (vPSG-hdEEG) suggests an association between sleep and some clinical phenotypes of Parkinson disease and a relationship between sleep disruption and levodopa-induced dyskinesia (05).
In a patient receiving antiparkinson drug therapy, it is often difficult to determine whether this disruption represents a primary neurobiological or a medication effect of Parkinson disease.
Two additional mechanisms by which sleep may be disturbed in Parkinson disease are the disruption of circadian rhythms and the appearance of parasomnias.
The appearance of a parasomnia, especially REM sleep behavior disorder, may antedate the onset of clinically apparent Parkinson disease (78). The appearance of a parasomnia, especially REM sleep behavior disorder, may antedate the onset of clinically apparent Parkinson disease (78). In idiopathic REM sleep behavior disorder subjects CD4+ T cells exhibit a peculiar molecular signature strongly resembling cells from Parkinson disease patients (27). Furthermore, α-synuclein (SNCA) hypomethylation in leukocytes existed both in patients with iRBD and those with Parkinson disease, indicating that α-synuclein methylation could be a potential biomarker for early Parkinson disease diagnosis (126).
The motor symptoms of Parkinson disease have significant potential to interrupt sleep. In this regard, either hyperkinetic or hypokinetic abnormalities can interfere with sleep onset or maintenance. One final mechanism of sleep disturbance relates to the medications used to treat Parkinson disease. These drugs can result in daytime sleepiness and nocturnal or early morning dystonia as well as contribute to the development of nocturnal hallucinations.
Dopamine deficiency is a major neurochemical change in Parkinson disease. Generally, dopaminergic stimulation is thought to promote wakefulness. Dopamine agonists have been found to suppress REM sleep in animals (107). However, single-cell recordings in nigral dopaminergic neurons do not exhibit major changes during the phases of the sleep-wake cycle (62). Observations such as these raise the possibility that other neurotransmitter changes in Parkinson disease may play a role in the genesis of sleep disorders. Moreover, alterations in brainstem nuclei, ie, coeruleus-subcoeruleus and gigantocellularis, that are present in Parkinson disease patients could explain the presence of REM behavior disorder (124). MRI studies document a smaller right putamen, left hippocampus, and left thalamus volume linked to REM sleep behavior disorder symptoms severity in Parkinson disease patients (46).
Norepinephrine and serotonin are both reduced in Parkinson disease (105). In a study with positron emission tomography, reduced serotonergic function in the midbrain raphe, basal ganglia, and hypothalamus was associated with sleep dysfunction in Parkinson disease (118).
Neuromelanin-sensitive imaging demonstrated reduced signal intensity in the locus coeruleus/subcoeruleus area that correlated with the percentage of abnormally increased muscle tone during REM sleep (39). Hypocretin cell loss has been demonstrated in the hypothalamus of Parkinson patients, CSF hypocretin has been found to be normal, reinforcing the notion that other mechanisms may contribute to excessive somnolence in this condition (23). Aberrations of cholinergic function in Parkinson disease may be important in the production of sleep disorders. The pedunculopontine nucleus contains cholinergic neurons that are thought to play an important role in the modulation of REM sleep, has reciprocal connections with the substantia nigra, and is known to be hyperactive in animal models of parkinsonism (72). Studies looking at PET imaging for cholinergic neurons found evidence of cholinergic denervation in patients with symptoms of REM sleep behavior disorder (50). Therefore, abnormalities of cholinergic function may be, in part, responsible for the increased incidence of REM sleep behavior disorder as well as for the disruption of sleep architecture found in patients with Parkinson disease. In Parkinson disease patients with excessive daytime sleepiness, current neuroimaging studies generally suggest diminished neural structural and functional features (eg, brain volume, white matter integrity as indicated by fractional anisotropy, and cerebral metabolism) (117). Sleep disturbances were associated with thalamic atrophy in 41 Parkinson disease patients, and an alteration of intra- and interregional functional connectivity of the anterior cingulate gyrus was related to sleep disorders in patients with tremor-dominant Parkinson disease (20; 67). Parkinson disease patients with nocturnal hallucinations have prominent basal ganglia volume reduction (81).
Parkinson disease patients with REM sleep behavior disorder show extensive cortical thinning in the perisylvian and temporal cortices and shape contraction in the basal ganglia, hippocampus, and thalamus, suggesting more severe neurodegeneration (46; 82).
Although there are some exceptions, sleep disorders associated with Parkinson disease tend to be more common and intense in older patients and in those with more severe clinical symptoms. With the exception of REM sleep behavior disorder, sleep disorders associated with Parkinson disease tend to occur later rather than earlier in the course of the illness.
To date, there are no proven means of delaying the onset or halting the progression of Parkinson disease. Once the illness is established, however, several strategies may be used to reduce the incidence of associated sleep disorders. Among these strategies including also a correct sleep-hygiene, is the judicious use of antiparkinsonian drugs, which includes:
(a) the use of those drugs with the least potential for producing daytime somnolence
(b) avoiding bedtime dosages of medications if not needed to reverse nocturnal immobility or tremor
(c) low dosages of dopaminergic drugs in order to reduce the incidence of dyskinesias and hallucinosis
The correct use of antiparkinsonian drugs, with a successful balance between side-effects and motor symptoms, is fundamental to reduce drug-related alterations of sleep in Parkinson patients. Thus, the improvement in daytime somnolence after replacing 1 dopaminergic medication with another confirms drug-induced somnolence. Improvement in nocturnal sleep efficiency after adding a dosage of sustained-release levodopa at bedtime helps confirm insomnia secondary to nocturnal rigidity and akinesia. Similarly, an improvement in excessive nocturnal motor activity after the addition of a bedtime dosage of clonazepam helps to confirm a diagnosis of REM sleep behavior disorder. Still, many forms of sleep disturbance require documentation by formal testing. Suspected sleep apnea should be assessed by formal polysomnography, as should insomnia and daytime somnolence that cannot be adequately diagnosed by the practical measures mentioned previously. For Parkinson disease patients with severe daytime somnolence, a 24-hour sleep/wake polygraphic recording could be useful to document the severity of this symptom. In some patients, documenting the relationship of daytime somnolence to medication dosing times is also beneficial. Additionally, these tests can be useful to document treatment success.
If the nature of the sleep disturbance can be correctly identified, there is an excellent chance that a beneficial therapeutic intervention can be undertaken.
Patients whose sleep is interrupted by extreme nocturnal rigidity benefit therapeutically from a bedtime dose of a dopaminergic agent with a relatively long efficacy half-life. A sustained-release levodopa preparation is possibly more useful. The use of a COMT-inhibiting agent along with levodopa at bedtime might further prolong the dopaminergic effect during the night. Bedtime dosing in these patients results in fewer awakenings, at least during the early part of the night and often through the entire night. Some patients may require an additional dose of a sustained-release or standard levodopa preparation after early awakening to allow uninterrupted sleep for the remainder of the night. The potential reintroduction of rotigotine, a dopamine agonist administered through a 24-hour transdermal patch (108; 110; 16; 32), or the administration of 24-hour prolonged-release dopamine agonist (85; 84) can be useful in providing some relief of sleep-disturbing motor symptoms during the entire night. Rasagiline (1 mg/day) showed beneficial effects on sleep quality as polysomnographically measured (94) and safinamide improved nocturnal sleep disturbances and daytime sleepiness as assessed by sleep questionnaires (52) in fluctuating Parkinson disease patients.
In the belief that antiparkinsonian medication is required around the clock, many Parkinson disease patients or their physicians initiate bedtime dosing of levodopa or a dopamine agonist in the absence of nocturnal motor symptoms or Parkinson disease-related sleep disturbance. This practice should be discouraged because it unnecessarily raises the dosages of medication. Dopaminergic drugs can also interfere with sleep by impairing sleep initiation or by inducing nocturnal dyskinesias or hallucinations in some patients. Bedtime dosing with dopaminergic medications can either improve or interfere with sleep. A clinical judgment in individual patients must be made to determine which effect is likely to prevail. In general, advanced Parkinson disease patients who experience nocturnal emergence of motoric symptoms are more likely to benefit from bedtime dosing. Milder patients have less to gain but stand a chance of experiencing medication-related sleep disturbance.
In patients who are severely disabled by nocturnal symptoms, but unable to get sufficient relief from these medical measures, deep brain stimulation of the subthalamic nucleus can be employed in some cases with good results (68; 43). Polysomnography and sleep questionnaires after deep brain stimulation revealed postoperative improvement in subjective and objective sleep quality (42; 22; 03; 87), with a reduction of the incidence of REM sleep without atonia and an improvement in quality of life and mood (68; 21; 26). Of interest, daytime sleepiness does not necessarily change after deep brain stimulation despite significant reduction of parkinsonian medications (54). Early morning dystonia can also be improved with bilateral deep brain stimulation (54). It remains elusive whether modulated activity in the subthalamic nucleus directly contributes to changes in sleep-wake behavior (11). Although it is possible that the procedure has a direct effect on sleep regulatory centers, much of the benefit can be explained by the improvement of nocturnal motor symptoms and the reduction in dosage of antiparkinsonian medications.
When insomnia is not related to motor or nonmotor Parkinson symptoms, eszopiclone, doxepin, zolpidem, trazodone, ramelteon, and melatonin could be useful, although these drugs are investigational in Parkinson disease because the evidence of their efficacy is insufficient (88).
In addition to pharmacological treatment of the sleep-disrupting motor features of Parkinson disease, several nonpharmacological strategies are also useful. To minimize the effect of nocturnal immobility, the use of satin sheets can be recommended as a means of reducing friction between the body and bed sheets, thereby allowing easier mobility in bed. Ambient stimuli (noises, drafts, a restless bed partner), which might lead to brief arousals followed by a major reemergence of tremor or rigidity and pain, should be avoided to the extent possible. Light-intensity exercise rehabilitation may be helpful in ameliorating the quality of sleep, as well as mood and cognition (86; 04).
Depression-related sleep disturbances in Parkinson disease are treated in much the same manner as those in the non-Parkinson disease population. The only minor differences include choices of drug. The sedating antidepressants such as amitriptyline or doxepin administered at bedtime are useful for this purpose. A randomized controlled trial demonstrated that doxepin (10 mg) at bedtime significantly improved both insomnia severity and sleep quality (88). For some Parkinson disease patients, especially those with dementia, agents with lower anticholinergic properties such as nortriptyline are a better choice in order to avoid exacerbating their cognitive deficit. Selective serotonin reuptake inhibitor (SSRI) drugs may be effective in treating depression and sleep-related symptoms in Parkinson disease (24). Also, the use of either SSRI or tricyclic antidepressants in patients receiving selegiline or rasagiline for Parkinson disease can cause a potentially serious interaction in a very small number of patients. Agomelatine in Parkinson disease depressed patients may have a considerable therapeutic potential because of its dual action for treating both symptoms of depression and disturbed sleep, reducing extrapyramidal symptoms (08).
Several strategies are available to help reverse the sleep cycle towards normalcy in Parkinson disease. An attempt should be made to restore mealtime to a typical morning, noon, and early evening pattern. Scheduled activities should be planned during times of predicted somnolence, whether drug-induced or related to the patient's spontaneous diurnal cycle. Light exposure is a promising medical treatment for improving sleep in Parkinson disease patients receiving dopaminergic therapies (58; 30). After exposing patients with Parkinson disease to bright or dim-red light twice daily, sleep and depressive symptoms improved, daytime sleepiness decreased, and Parkinson-specific motor scores were reduced (113; 101).
The sedating effects of antiparkinson medication can be countered to a slight extent by administration of a daytime dosage of selegiline. Despite the lack of clear evidence of the effect of pharmacological treatment of excessive daytime sleepiness in Parkinson disease patients (89), stimulant agents such as methylphenidate or dextroamphetamine are occasionally used, but tachyphylaxis and the occasional induction of hallucinosis in the elderly or cognitively impaired Parkinson disease patient limit their use. The adverse behavioral effects of these wake-promoting drugs in Parkinson disease might be avoided through the use of modafinil, which appears to have little or no dopaminergic activity and to reduce daytime sleepiness and fatigue (29). Early reports of the usefulness of this agent in Parkinson disease patients were favorable, but a double-blind study suggested that this agent was no different than placebo in improving excessive daytime sleepiness in Parkinson patients (71). Sodium oxybate was found to be useful in enhancing slow-wave sleep as well as in reducing daytime somnolence and fatigue (15).
Medication-induced somnolence can be difficult to correct. One simple strategy is to lower the daily dose. Another, mentioned earlier, is to alter environmental stimuli and planned activity schedules in the immediate post-dose period when somnolence is most likely to occur. During this at-risk period, dark, quiet, poorly ventilated rooms should be avoided, and planned vigorous activities such as a morning or afternoon walk should be scheduled. Fortunately, many Parkinson disease patients are best able to engage in such physically demanding activities immediately after a dosage of medication, when they are "on." An attempt can also be made to change to another antiparkinson drug. Some patients may be less somnolent on standard carbidopa or levodopa than on the sustained-release preparation. In a small percentage of patients, the reverse is true. Similarly, the available dopamine agonists may each have different potential to induce somnolence or “sleep attacks” in a given patient, so changing from 1 agent to another is a reasonable strategy. Reducing the agonist dosage, if clinically feasible, is also an effective strategy for many patients. Lastly, stimulant drugs, especially modafinil, have sometimes been found to be useful to combat this form of excessive daytime sleepiness in Parkinson disease.
Drug-induced hallucination treatment begins with a systematic withdrawal of dopaminergic drugs, beginning with the least clinically potent agents such as anticholinergics, amantadine, and selegiline. Next, a reduction or discontinuation of levodopa and dopamine agonists may be considered, although it is not always possible because of reemergence of serious parkinsonian symptoms. In this case, a relatively small bedtime dosage of the atypical antipsychotic agent quetiapine could be used. Quetiapine also improved sleep in Parkinson disease patients without hallucinations or psychosis, whereas 2 other atypical antipsychotic agents, olanzapine and risperidone, seem to be less effective for this purpose because they retain some ability to worsen Parkinson disease. If these strategies fail, low dosages of the atypical neuroleptic clozapine (12.5 to 50 mg per day) can be administered. Both of these agents can cause daytime somnolence if taken at any time other than at bedtime. Clozapine must be used with caution because of its potential to induce agranulocytosis and request periodic controls of blood-cell counts.
Because nocturnal or early morning dystonia is most commonly related to the waning central effect of the previous dosage of levodopa as the night progresses, the most useful treatment is to institute bedtime therapy with a relatively long-acting dopaminergic agent such as controlled release carbidopa-levodopa or a long-acting dopamine agonist. In some patients, a bedtime dosage of baclofen will also ameliorate this symptom. An additional strategy employed by some patients to prevent early morning dystonia is to set their alarm so that they can administer a dose of levodopa 30 to 45 minutes earlier than their usual waking time and then return to sleep to awaken permanently after the medication has begun to take effect.
Because of the potential for serious injury to the patient and for disruption of both the patient's and bed partner's sleep, serious attention should be given to treating REM sleep behavior disorder in Parkinson disease. The potential for injury while acting out a dream is even greater than average in Parkinson disease patients because they may fall if they attempt to stand in the middle of the night when antiparkinsonian medications have worn off. Parkinson disease patients with REM sleep behavior disorder are treated in much the same way as in non-Parkinson disease patients, namely clonazepam, at bedtime. Because of the long efficacy half-life of clonazepam, a bedtime dosage can result in daytime somnolence. Accordingly, it is often useful to experiment with dosage times as far in advance of bedtime as possible in order to avoid this potential complication. Melatonin improves sleep quality in patients with neurodegenerative disorders and can be considered as a possible mono or add-on therapy in patients with REM sleep behavior disorder (125; 01). Nevertheless, in a study on 30 Parkinson disease patients with REM sleep behavior disorder, prolonged-release melatonin 4 mg did not reduce REM sleep behavior disorder (40). Ramelteon was effective in REM sleep behavior disorder in Parkinson disease patients in 2 open trials, which were conducted in 24 and 12 Parkinson disease patients, respectively (31). Daytime sleepiness, nausea, delirium, giddiness, and worsening of constipation are possible ramelteon side effects.
In patients with obstructive sleep apnea, CPAP treatment can improve overall nonmotor symptoms, sleep quality, and global cognitive function (45).
Many of the sleep disturbances associated with Parkinson disease are amenable to reversal, although others are not. Conditions such as insomnia related to nocturnal immobility, nocturnal hallucinosis, and REM sleep behavior disorder can often be reversed with appropriate therapeutic interventions. Daytime somnolence has the worst prognosis for improvement, especially when related to medication. Often, patients suffering this adverse effect note that virtually all of the dopaminergic medications act similarly to induce somnolence, although discontinuing all dopaminergic medications during the day is not a viable option for most of these patients.
Pregnancy is rare in the Parkinson disease population, given the older age distribution of the condition.
Parkinson disease may be temporarily exacerbated after a major surgical procedure, especially with the use of general anesthesia or major sedation.
Federica Provini MD
Dr. Provini of the University of Bologna and IRCCS Institute of Neurological Sciences of Bologna received speakers' fees from Italfarmaco and Pfizer.See Profile
Giuseppe Loddo MD
Dr. Loddo of the University of Bologna has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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