**8. Nocturnal sleep disorders**

## **8.1 Insomnia**

Insomnia affects approximately 50 to 60% of patients with PD, making it the most common sleep disorder and perhaps the most complex to treat given its multifaceted basis [42]. When it lasts for more than three months, it is considered chronic insomnia [43].

It can be further classified into the following patterns:


Decreased total sleep time Increased sleep latency Increased sleep fragmentation Increase WASO Decreased sleep efficiency Decreased spindles Decreased N3 stage Decreased REM stage

*WASO: wake after sleep onset. N3; NREM slow waves stage [41].*

#### **Table 5.** *Sleep architecture in PD.*

The most common insomnia is sleep-maintenance insomnia seen in 80 percent of patient with PD, whereas sleep onset and terminal insomnia are seen in 18 percent and 40 percent of the PD patients, respectively [36, 37, 44, 45]. Insomnia is more prevalent in women, those with longer PD duration, and those with depression or anxiety. The causes of insomnia is multifactorial and includes the neurodegenerative process of PD itself, co-morbid sleep disorders, nocturia, cramps, limitation in mobility (i.e. difficulty turning in bed), early morning leg dystonia, pain, confusion, urinary dysfunction, sleep breathing disorders [SBD], and drugs [36, 42, 45, 46, 47]. Circadian rhythm disorders and psychiatric disorders [depression, anxiety, hallucinations, etc.] may also contribute in the genesis of insomnia [45–47].

Before deciding on a treatment option for insomnia, it is important to establish the specific pattern of insomnia and other risk factors that may be contributing to the condition. For example, addressing motor symptoms and/or obstructive sleep apnea may significantly improve insomnia therefore reducing or even eliminating the need for pharmacological interventions.

Almost half of patients with PD take medications for insomnia [36, 37, 42]. The use of levodopa-carbidopa controlled release [LD-CD] at bedtime may reduce motor bradykinesia/akinesia with improvement in total sleep time [48]. Dopamine agonists [DA] such as ropinirole-24 hour prolonged release (2-24 mg/day) [49], pramipexole (up to 4.5 mg/day) and transdermal rotigotine patch (up to 16 mg/day) [50] can be used as adjuncts to LD-CD. This combination has shown to improve both nocturnal motor activity and sleep symptoms. Two trials with transdermal rotigotine patch demonstrated improvement not only nocturnal motor symptoms but also wake time after sleep onset [WASO], nocturia, pain, RLS with reduced daily sleep episodes and overall improved quality of life in PD patients [51, 52]. MAO-inhibitor rasagiline has shown to improve total sleep time and reduce sleep latency when used in combination with LD-CD compare to when LD-CD is used alone [53]. Rasagiline's beneficial effects on insomnia are likely related to an increment in melatonin levels.

After motor impairment and co-existent sleep disorders are identified and treated, insomnia can further be managed with cognitive behavioral therapy utilizing sleep hygiene techniques, stimulus control, sleep restriction, relaxation techniques, and cognitive therapy [53, 54]. Soporific drugs such as eszopiclone, zolpidem, doxepin, trazodone, ramelteon, and melatonin have been used with various success in the therapy of insomnia in PD patients [44]. Melatonin at very high doses (50 mg) at bedtime was compared with 5 mg/day at the bedtime in the treatment of insomnia in PD patients. Melatonin 50 mg dose showed a statistical significant improvement in total sleep time compared to lower doses, however melatonin at 5 mg improved subjective sleep disturbance, sleep quantity, and daytime drowsiness compared to placebo. Melatonin may be associated with morning headaches, hallucination, and daily drowsiness [55].

**61**

*The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep…*

Nocturia is defined as an increase in the frequency of nocturnal urination. About one third of PD patients suffer from nocturia [56]. Nocturia in PD is most likely a result of autonomic dysfunction caused by detrusor hyperreflexia from lack of dopamine which decreases the inhibition of micturition. However, it is important to rule out secondary organic causes of nocturia (such as urinary tract infections, prostrate disorders, anxiety, congestive heart failure, etc.) before altering anti-

Subcutaneous apomorphine at a dose of 3-8 mg at bedtime has been used to treat nocturia as it reduces the hyperreflexia in the detrusor muscles [57]. Rasagiline at a dose of 1 mg/day can increase bladder capacity and decreases residual volume [58]. Intranasal desmopressin and botulinum toxins in the detrusor muscles may be beneficial. Anticholinergic drugs [oxybutynin, solifenacin, darifenacin, tolterodine], can potentially help with nocturia, although the side effects of these drugs

(drowsiness and cognitive impairment) might be an impediment [35].

Restless leg syndrome [RLS] is a sensorimotor disorder characterized by an unpleasant leg sensation associated with an urge to move the legs, relieved by leg movement, worsen by inactivity and worse at night [43]. RLS is seen in about 20% of patients with PD, which is a higher rate than in the general population [59]. Primary RLS is a genetic disorder, whereas secondary RLS results from other conditions such as renal disease, iron deficiency, co-existence of neuropathies, medications, etc. [43, 60]. PD patients who develop RLS tend to have later PD onset, poor sleep quality and more cardiovascular and anxiety disorders [45, 59]. RLS need to be differentiated from common complain seen in PD patients such as uncomfortable nocturnal motor symptoms secondary to immobility, akathisia and dystonia. The treatment of RLS in PD patients is similar to the treatment for non-PD patients. Identify and treat any underlying secondary causes of RLS first. Iron supplementation is required when ferritin levels are below 50 microg/ml. Antidepressants may worsen RLS symptoms therefore adjustment in dosage or replacement with bupropion with dopaminergic effect is warranted [60, 61]. Antidopaminergic and antihistaminic medications can also worsen RLS [45]. L-dopa-carbidopa is no longer recommended to treat RLS due to the high risk of augmentation (treatment complication from dopaminergic drug with worsening of the RLS symptoms [45, 60, 61]. Dopamine agonists (ropinirole, pramipexole, transdermal rotigotine patches) and GABAergic products (pregabalin, enacarbil, gabapentin) can be used as first line of therapy. The latter being particularly useful in patients with a coexistent neuropathic pain [60, 61]. Other drugs as clonazepam and opioids may be used to induce sleep and treat pain, respectively. New devices that apply pressure to the

Periodic leg moment of the sleep [PLMS] is a sleep disorder characterized by repetitive leg movements while patient is asleep that result in sleep fragmentation and daily drowsiness. Whereas the diagnosis of RLS is clinical the diagnosis of PLMS is polysomnographic. A PLMS index [leg movements per hour of sleep] of 15 or more is considerate abnormal [43]. PLMS is seen in 80% of patients with RLS [43] and the incidence of PLMS is 30–80% of patients with Parkinson disease [45, 63].

*DOI: http://dx.doi.org/10.5772/intechopen.98934*

Parkinson medication doses [45, 48].

legs may also relieve RLS symptoms [62].

**8.4 Periodic leg moment of sleep**

**8.3 Restless leg syndrome**

**8.2 Nocturia**

*The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep… DOI: http://dx.doi.org/10.5772/intechopen.98934*

### **8.2 Nocturia**

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

*WASO: wake after sleep onset. N3; NREM slow waves stage [41].*

Decreased total sleep time Increased sleep latency Increased sleep fragmentation

Increase WASO Decreased sleep efficiency Decreased spindles Decreased N3 stage Decreased REM stage

*Sleep architecture in PD.*

**Table 5.**

The most common insomnia is sleep-maintenance insomnia seen in 80 percent of patient with PD, whereas sleep onset and terminal insomnia are seen in 18 percent and 40 percent of the PD patients, respectively [36, 37, 44, 45]. Insomnia is more prevalent in women, those with longer PD duration, and those with depression or anxiety. The causes of insomnia is multifactorial and includes the neurodegenerative process of PD itself, co-morbid sleep disorders, nocturia, cramps, limitation in mobility (i.e. difficulty turning in bed), early morning leg dystonia, pain, confusion, urinary dysfunction, sleep breathing disorders [SBD], and drugs [36, 42, 45, 46, 47]. Circadian rhythm disorders and psychiatric disorders [depression, anxiety, halluci-

Before deciding on a treatment option for insomnia, it is important to establish the specific pattern of insomnia and other risk factors that may be contributing to the condition. For example, addressing motor symptoms and/or obstructive sleep apnea may significantly improve insomnia therefore reducing or even eliminating

Almost half of patients with PD take medications for insomnia [36, 37, 42]. The use of levodopa-carbidopa controlled release [LD-CD] at bedtime may reduce motor bradykinesia/akinesia with improvement in total sleep time [48]. Dopamine agonists [DA] such as ropinirole-24 hour prolonged release (2-24 mg/day) [49], pramipexole (up to 4.5 mg/day) and transdermal rotigotine patch (up to 16 mg/day) [50] can be used as adjuncts to LD-CD. This combination has shown to improve both nocturnal motor activity and sleep symptoms. Two trials with transdermal rotigotine patch demonstrated improvement not only nocturnal motor symptoms but also wake time after sleep onset [WASO], nocturia, pain, RLS with reduced daily sleep episodes and overall improved quality of life in PD patients [51, 52]. MAO-inhibitor rasagiline has shown to improve total sleep time and reduce sleep latency when used in combination with LD-CD compare to when LD-CD is used alone [53]. Rasagiline's beneficial

nations, etc.] may also contribute in the genesis of insomnia [45–47].

effects on insomnia are likely related to an increment in melatonin levels.

After motor impairment and co-existent sleep disorders are identified and treated, insomnia can further be managed with cognitive behavioral therapy utilizing sleep hygiene techniques, stimulus control, sleep restriction, relaxation techniques, and cognitive therapy [53, 54]. Soporific drugs such as eszopiclone, zolpidem, doxepin, trazodone, ramelteon, and melatonin have been used with various success in the therapy of insomnia in PD patients [44]. Melatonin at very high doses (50 mg) at bedtime was compared with 5 mg/day at the bedtime in the treatment of insomnia in PD patients. Melatonin 50 mg dose showed a statistical significant improvement in total sleep time compared to lower doses, however melatonin at 5 mg improved subjective sleep disturbance, sleep quantity, and daytime drowsiness compared to placebo. Melatonin may be associated with morning headaches,

the need for pharmacological interventions.

hallucination, and daily drowsiness [55].

**60**

Nocturia is defined as an increase in the frequency of nocturnal urination. About one third of PD patients suffer from nocturia [56]. Nocturia in PD is most likely a result of autonomic dysfunction caused by detrusor hyperreflexia from lack of dopamine which decreases the inhibition of micturition. However, it is important to rule out secondary organic causes of nocturia (such as urinary tract infections, prostrate disorders, anxiety, congestive heart failure, etc.) before altering anti-Parkinson medication doses [45, 48].

Subcutaneous apomorphine at a dose of 3-8 mg at bedtime has been used to treat nocturia as it reduces the hyperreflexia in the detrusor muscles [57]. Rasagiline at a dose of 1 mg/day can increase bladder capacity and decreases residual volume [58]. Intranasal desmopressin and botulinum toxins in the detrusor muscles may be beneficial. Anticholinergic drugs [oxybutynin, solifenacin, darifenacin, tolterodine], can potentially help with nocturia, although the side effects of these drugs (drowsiness and cognitive impairment) might be an impediment [35].

### **8.3 Restless leg syndrome**

Restless leg syndrome [RLS] is a sensorimotor disorder characterized by an unpleasant leg sensation associated with an urge to move the legs, relieved by leg movement, worsen by inactivity and worse at night [43]. RLS is seen in about 20% of patients with PD, which is a higher rate than in the general population [59]. Primary RLS is a genetic disorder, whereas secondary RLS results from other conditions such as renal disease, iron deficiency, co-existence of neuropathies, medications, etc. [43, 60]. PD patients who develop RLS tend to have later PD onset, poor sleep quality and more cardiovascular and anxiety disorders [45, 59]. RLS need to be differentiated from common complain seen in PD patients such as uncomfortable nocturnal motor symptoms secondary to immobility, akathisia and dystonia. The treatment of RLS in PD patients is similar to the treatment for non-PD patients. Identify and treat any underlying secondary causes of RLS first. Iron supplementation is required when ferritin levels are below 50 microg/ml. Antidepressants may worsen RLS symptoms therefore adjustment in dosage or replacement with bupropion with dopaminergic effect is warranted [60, 61]. Antidopaminergic and antihistaminic medications can also worsen RLS [45]. L-dopa-carbidopa is no longer recommended to treat RLS due to the high risk of augmentation (treatment complication from dopaminergic drug with worsening of the RLS symptoms [45, 60, 61]. Dopamine agonists (ropinirole, pramipexole, transdermal rotigotine patches) and GABAergic products (pregabalin, enacarbil, gabapentin) can be used as first line of therapy. The latter being particularly useful in patients with a coexistent neuropathic pain [60, 61]. Other drugs as clonazepam and opioids may be used to induce sleep and treat pain, respectively. New devices that apply pressure to the legs may also relieve RLS symptoms [62].

#### **8.4 Periodic leg moment of sleep**

Periodic leg moment of the sleep [PLMS] is a sleep disorder characterized by repetitive leg movements while patient is asleep that result in sleep fragmentation and daily drowsiness. Whereas the diagnosis of RLS is clinical the diagnosis of PLMS is polysomnographic. A PLMS index [leg movements per hour of sleep] of 15 or more is considerate abnormal [43]. PLMS is seen in 80% of patients with RLS [43] and the incidence of PLMS is 30–80% of patients with Parkinson disease [45, 63].

Age and dopamine loss may contribute to PLMS [64]. The mainstay treatment for PLM is the use of dopamine agonists [65].

### **8.5 REM behavior disorder**

REM Behavior Disorder (RBD) is a REM-parasomnia characterized by the ability of the patient to reenact the content of his dreams with complex and violent motor behaviors which varies from vocalization, throwing punches, kicking, flailing, screaming, to jumping from the bed and running. This can cause injuries to the patient and/or to the bed partners [43]. RBD is commonly seen in PD [66] and is more prevalent in the second half of the night when REM sleep occurs [43]. Studies have demonstrated that RBD may manifest years prior to the development of PD symptoms with an estimated 75–90% of RBD patients developing PD after 10 to 14 years from onset [43]. RBD may precede the onset of others alpha-synucleinopathies such as Lewy Body dementia and multiple system atrophy [43]. RBD should be considered in patients presenting with history of "acting out their dreams or motor activation while sleeping" and confirm it with video polysomnography, though not require for its diagnosis. Creating a safe sleeping environment is the first step in management. This condition responds to low dose of clonazepam [0.25-2 mg qhs]. Clonazepam improves total sleep time, sleep efficiency, increase in NREM sleep, and decrease WASO [67, 68]. However, this medication was associated with sedation, cognitive deficits, and increments in falls [45]. Melatonin 3 to 12 mg at night or at higher doses is also helpful in RBD and can be used with dementia and obstructive sleep apnea where clonazepam is not recommended. Melatonin may be used as solo or co-adjuvant therapy for insomnia and at high doses may be associated with morning headaches, sedation, or delusion/hallucinations [45, 69]. Patients who failed clonazepam and melatonin may respond to rivastigmine [70] or ramelteon [71] at night.

### **8.6 Sleep-breathing disorders**

Obstructive sleep apnea (OSA) is the most common sleep breathing disorder (SBD). Other forms of SBDs are also seen in PD such as snoring, central and mixed apneas [43]. OSA is characterized by intermittent and repetitive events of pharyngeal airway collapse with complete upper airway obstruction (apnea) or partial upper airway obstruction (hypopneas) during sleep, especially during REM sleep when the effect of the atonia is more pronounced. Patients present with nocturnal snoring, snorting, sleep fragmentation, insomnia, and daily consequences of daytime sleepiness, fatigue, poor concentration, poor memory, and mood changes. If severe, it is associated with sleep attacks [spells of sudden sleepiness] [43]. The prevalence of OSA in PD varies between 20–60% depending on the methodology used to score respiratory events [45] and according to two recent studies it is more common in PD patients than in the general population [72, 73]. An additional study showed that SBDs are also more common in other forms of parkinsonism such as vascular parkinsonism than controls [74]. From all forms of SBDs [snoring, central sleep apneas and obstructive sleep apneas] OSA is the most common form in PD [74]. This is likely related to multiple factors seen in patients with PD: most PD patients are elders [advanced age is a risk factor for OSA], PD present with autonomic dysfunction [autonomic dysfunction increases the risk for OSA], PD patients share loss of motor neurons from brainstem involved in respiration [reduced respiratory drive] and control oropharyngeal muscles [fluctuating respiratory muscle coordination increases risk for OSA], PD patients have restrictive lung disease caused by chest wall rigidity and upper airway abnormalities as shown spirometry

**63**

*The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep…*

abnormalities in up 65% patients with PD [75]which increased the risk for upper airway obstruction [42, 74]. The diagnosis of OSA is suspected through history and specific screening questionnaires such as STOP-BANG and Berlin's questionnaire. In PD, STOP-BANG has a high sensitivity, but low specificity in the diagnosis of OSA, whereas the Berlin's Questionnaire has a higher sensitivity in the diagnose of PD, but it sensitivity declines as the severity of PD declines [76]. And it is confirmed with polysomnography at a sleep center or level III portable monitoring at home [77, 78]. OSA may worsen PD as it worsens sleep fragmentation and causes intermittent hypoxia [45, 79, 80] which is associated with worsening in the cognitive function [81, 82]. Sleep disorders are considered one of the most disabling of the non-motor symptoms of PD [83]. The treatment of OSA with PD is the same than in patients without PD: body weight loss, positional therapy, continuous positive airway pressure (CPAP), and surgery [45, 84]. The cognitive impairment often reported in patient with Parkinson disease [81, 82] also improves with positive airway pressure

Circadian rhythm disorders (CRD) are implicated in the pathophysiology of PD [86], but their real prevalence in PD patients remains unknown [87]. Motor and non-motor features [autonomic function, visual performance, sleep-awake cycles, and response to dopaminergic drugs] experienced a diurnal fluctuation from the circadian system [88]. Dopamine is an intermediary of light providing input to the retinal circadian clock which provides a direct input to the suprachiasmatic nuclei (SCN). Thereby, via retinal dopamine-containing amacrine cells, information is conveyed across a series of clock genes that control the circadian rhythm. Dopamine deficiency, seen in Parkinson disease, affects specific clock genes (dysregulation of Bmal gene expression) resulting in dysfunction of the central sleep–wake cycle control [86, 87]. Studies using actigraphy to record times of wrist motor activity [wakefulness] and times of motor inactivity [sleepiness] showed lower peaks of physical activity during rest time and higher levels of activity at night compared with control [89, 90]. Motor symptoms in Parkinson disease worsen in the afternoon and evening in stable patients and patients with wearing off [advanced PD] indicating that the response to dopaminergic drugs declines throughout the daytime [91]. This decrease in diurnal activity and increase in nocturnal activity observed in PD patients is influenced by dopaminergic drugs [86]. A variability in the pharmacokinetics of levodopa, i.e. faster during daytime and while standing compared with being supine at night, play the role in levodopa variability [92]. Patient with PD with hallucinations show more fragmentation of the rest activity with more

Autonomic dysfunction, a common feature in PD, also follows a circadian pattern with a nocturnal blood pressure reversal pattern i.e. blood pressure equal or higher than daytime blood pressure as demonstrated in most of the patients in one study [94]. An attenuation of sympathetic nervous system activity in PD patients was demonstrated by a heart rate variability study where power spectral analysis using a 24-hour ambulatory EKG revealed a decrease in total frequency component and low frequency/high frequency ratio [86, 94]. Studies in PD patients have shown a reduction in core body temperature. This reduction in core temperature correlated with higher rates of self-reported RBD symptoms, reduction in percentage of REM

Hormonal changes are also affected by circadian rhythms in PD. PD patients have shown elevated serum cortisol levels and reduced serum melatonin levels compared with controls [96, 97]. Furthermore, melatonin diurnal fluctuations are

*DOI: http://dx.doi.org/10.5772/intechopen.98934*

therapy [85].

**8.7 Circadian rhythm disorder**

unpredictability in the circadian pattern [93].

sleep, and prolonged latency compared with controls [95].

*The Relationship between Amyotrophic Lateral Sclerosis and Parkinson's Disease and Sleep… DOI: http://dx.doi.org/10.5772/intechopen.98934*

abnormalities in up 65% patients with PD [75]which increased the risk for upper airway obstruction [42, 74]. The diagnosis of OSA is suspected through history and specific screening questionnaires such as STOP-BANG and Berlin's questionnaire. In PD, STOP-BANG has a high sensitivity, but low specificity in the diagnosis of OSA, whereas the Berlin's Questionnaire has a higher sensitivity in the diagnose of PD, but it sensitivity declines as the severity of PD declines [76]. And it is confirmed with polysomnography at a sleep center or level III portable monitoring at home [77, 78]. OSA may worsen PD as it worsens sleep fragmentation and causes intermittent hypoxia [45, 79, 80] which is associated with worsening in the cognitive function [81, 82]. Sleep disorders are considered one of the most disabling of the non-motor symptoms of PD [83]. The treatment of OSA with PD is the same than in patients without PD: body weight loss, positional therapy, continuous positive airway pressure (CPAP), and surgery [45, 84]. The cognitive impairment often reported in patient with Parkinson disease [81, 82] also improves with positive airway pressure therapy [85].

#### **8.7 Circadian rhythm disorder**

*Updates in Sleep Neurology and Obstructive Sleep Apnea*

PLM is the use of dopamine agonists [65].

**8.5 REM behavior disorder**

Age and dopamine loss may contribute to PLMS [64]. The mainstay treatment for

REM Behavior Disorder (RBD) is a REM-parasomnia characterized by the ability of the patient to reenact the content of his dreams with complex and violent motor behaviors which varies from vocalization, throwing punches, kicking, flailing, screaming, to jumping from the bed and running. This can cause injuries to the patient and/or to the bed partners [43]. RBD is commonly seen in PD [66] and is more prevalent in the second half of the night when REM sleep occurs [43]. Studies have demonstrated that RBD may manifest years prior to the development of PD symptoms with an estimated 75–90% of RBD patients developing PD after 10 to 14 years from onset [43]. RBD may precede the onset of others alpha-synucleinopathies such as Lewy Body dementia and multiple system atrophy [43]. RBD should be considered in patients presenting with history of "acting out their dreams or motor activation while sleeping" and confirm it with video polysomnography, though not require for its diagnosis. Creating a safe sleeping environment is the first step in management. This condition responds to low dose of clonazepam [0.25-2 mg qhs]. Clonazepam improves total sleep time, sleep efficiency, increase in NREM sleep, and decrease WASO [67, 68]. However, this medication was associated with sedation, cognitive deficits, and increments in falls [45]. Melatonin 3 to 12 mg at night or at higher doses is also helpful in RBD and can be used with dementia and obstructive sleep apnea where clonazepam is not recommended. Melatonin may be used as solo or co-adjuvant therapy for insomnia and at high doses may be associated with morning headaches, sedation, or delusion/hallucinations [45, 69]. Patients who failed clonazepam and melatonin may respond to rivastigmine [70] or ramelteon

Obstructive sleep apnea (OSA) is the most common sleep breathing disorder (SBD). Other forms of SBDs are also seen in PD such as snoring, central and mixed apneas [43]. OSA is characterized by intermittent and repetitive events of pharyngeal airway collapse with complete upper airway obstruction (apnea) or partial upper airway obstruction (hypopneas) during sleep, especially during REM sleep when the effect of the atonia is more pronounced. Patients present with nocturnal snoring, snorting, sleep fragmentation, insomnia, and daily consequences of daytime sleepiness, fatigue, poor concentration, poor memory, and mood changes. If severe, it is associated with sleep attacks [spells of sudden sleepiness] [43]. The prevalence of OSA in PD varies between 20–60% depending on the methodology used to score respiratory events [45] and according to two recent studies it is more common in PD patients than in the general population [72, 73]. An additional study showed that SBDs are also more common in other forms of parkinsonism such as vascular parkinsonism than controls [74]. From all forms of SBDs [snoring, central sleep apneas and obstructive sleep apneas] OSA is the most common form in PD [74]. This is likely related to multiple factors seen in patients with PD: most PD patients are elders [advanced age is a risk factor for OSA], PD present with autonomic dysfunction [autonomic dysfunction increases the risk for OSA], PD patients share loss of motor neurons from brainstem involved in respiration [reduced respiratory drive] and control oropharyngeal muscles [fluctuating respiratory muscle coordination increases risk for OSA], PD patients have restrictive lung disease caused by chest wall rigidity and upper airway abnormalities as shown spirometry

**62**

[71] at night.

**8.6 Sleep-breathing disorders**

Circadian rhythm disorders (CRD) are implicated in the pathophysiology of PD [86], but their real prevalence in PD patients remains unknown [87]. Motor and non-motor features [autonomic function, visual performance, sleep-awake cycles, and response to dopaminergic drugs] experienced a diurnal fluctuation from the circadian system [88]. Dopamine is an intermediary of light providing input to the retinal circadian clock which provides a direct input to the suprachiasmatic nuclei (SCN). Thereby, via retinal dopamine-containing amacrine cells, information is conveyed across a series of clock genes that control the circadian rhythm. Dopamine deficiency, seen in Parkinson disease, affects specific clock genes (dysregulation of Bmal gene expression) resulting in dysfunction of the central sleep–wake cycle control [86, 87]. Studies using actigraphy to record times of wrist motor activity [wakefulness] and times of motor inactivity [sleepiness] showed lower peaks of physical activity during rest time and higher levels of activity at night compared with control [89, 90]. Motor symptoms in Parkinson disease worsen in the afternoon and evening in stable patients and patients with wearing off [advanced PD] indicating that the response to dopaminergic drugs declines throughout the daytime [91]. This decrease in diurnal activity and increase in nocturnal activity observed in PD patients is influenced by dopaminergic drugs [86]. A variability in the pharmacokinetics of levodopa, i.e. faster during daytime and while standing compared with being supine at night, play the role in levodopa variability [92]. Patient with PD with hallucinations show more fragmentation of the rest activity with more unpredictability in the circadian pattern [93].

Autonomic dysfunction, a common feature in PD, also follows a circadian pattern with a nocturnal blood pressure reversal pattern i.e. blood pressure equal or higher than daytime blood pressure as demonstrated in most of the patients in one study [94]. An attenuation of sympathetic nervous system activity in PD patients was demonstrated by a heart rate variability study where power spectral analysis using a 24-hour ambulatory EKG revealed a decrease in total frequency component and low frequency/high frequency ratio [86, 94]. Studies in PD patients have shown a reduction in core body temperature. This reduction in core temperature correlated with higher rates of self-reported RBD symptoms, reduction in percentage of REM sleep, and prolonged latency compared with controls [95].

Hormonal changes are also affected by circadian rhythms in PD. PD patients have shown elevated serum cortisol levels and reduced serum melatonin levels compared with controls [96, 97]. Furthermore, melatonin diurnal fluctuations are blunted in PD patients [98] which correlates with the self-reported symptoms of EDS [97]. The amplitude in melatonin decreases and melatonin phase advanced in PD treated patients compared with non-treated patients indicating that as PD progresses melatonin decreases with a phase advancement [99]. Dopamine drugs affect the regulation of melatonin circadian pattern and sleep onset patients in PD patients [100].

Circadian rhythm changes affect also visual performance in PD [101] most likely caused by impairment in retinal dopamine content that follows a circadian rhythm independent of light/dark cycles [102] Dopamine agonists may regulate the rhythmic expression of melanopsin in retina ganglion cells [88].

In summery the causes of CRD in PD are multifactorial and some are included below list:


Light therapy is a non-invasive technique proven to be safe, well tolerated, and effective on the treatment of daily drowsiness and impair alertness in PD [104–106].
