Correlations Between Premorbid Sleep Disturbances and the Onset of Parkinson’s Disease, Research Paper Example

 Introduction

Studies are beginning to identify a relationship between sleep disorders or sleep disturbances and the development of Parkinson’s disease (PD). For example, in 2006 Chen, Schernhammer, Schwarzchild, and Ascherio (2006) noted that nurses with an extensive work history of working rotating night shifts had a 50% lower likelihood of developing PD than those nurses who, over the same time period, never worked rotating night shifts. These authors also found that longer sleep duration was positively associated with Parkinson’s disease risk, and noted that sleep problems may predate any discernible motor symptoms that are generally associated with PD (Chen et al., 2006). A year later, Manni, Terzaghi, Pacchetti, and Nappi (2007) noted that disturbances in sleep and excessive sleepiness in daytime are considered premorbid symptoms for PD. Tools such as the Parkinson’s Disease Sleep Scale (PDSS) and the Short and Practical (SCOPA) Sleep Scale are used to evaluate the sleep patterns of PD patients (Manni et al., 2007).

PD is commonly associated with a variety of nonmotor symptoms as well as the more evident motor control dysfunctions. Traditionally, PD has been considered to begin in the substantia nigra, which leads to the motor control dysfunctions, but nonmotor symptoms may not follow that traditional view (Tolosa & Pont-Sunyer, 2011). Instead, the source of these symptoms can be identified with problems in the cortex, including cognitive impairment and psychosis issues; with the basal ganglia, including impulse control issues, apathy, and restlessness; with the spinal column, including orthostatic hypotension and urological problems; with the peripheral nervous system, including issues with pain and constipation; and with the brainstem, including depression, anxiety and sleep disorders (Stacy, 2011; Stavitsky et al., 2012). In particular with respect to sleep disorders in PD patients, investigations have documented less total time spent asleep, less sleep efficiency, more frequent awakenings, and overall greater time awake compared to non-PD patients (Stacy, 2011). One sleep symptom in particular that is frequently associated with PD is rapid eye movement (REM) behavior disorder (RBD) (Tolosa & Pont-Sunyer, 2011). The presence of some of these symptoms can appear years or even decades prior to the development of PD itself ( Tolosa & Pont-Sunyer, 2011).

In the literature review that follows more recent studies that consider the evidence for the comorbidities of sleep disorders and pre-motor PD to identify the mechanisms involved in such correlations between extended sleep and sleepiness and early stages of PD.

Premotor Symptoms and Early Diagnosis of Parkinson’s

One of the critical aims guiding research into correlational studies of sleep patterns and early-stage PD is the goal of developing diagnostic criteria that can reliably detect neurodegeneration and thus enable an early beginning to neuroprotective and neuromodulatory therapies. Typical of the types of premotor symptoms that occur among PD patients are issues such as hyposmia, sleep disorders, autonomic abnormalities, cognitive changes, and neurobehavioral changes (Adler, 2011). The implication is that PD is not a single disease but rather a syndrome of multiple conditions, possibly with multiple etiologies (Adler, 2011). Neurological issues that often precede motor symptoms include loss of olfactory discrimination, though this is also present in other degenerative diseases such as Alzheimer’s and multiple system atrophy (Adler, 2011). PD patients often complain of blurred vision, difficulty with color discrimination, and contrast sensitivity, and various autonomic dysfunctions, including constipation, abnormal cardiac functioning, orthostatic hypotension (i.e., sudden dizziness when standing), and variable heart rhythms (Adler, 2011). Mild cognitive impairment may also precede motor symptoms in PD patients (Adler, 2011). The most accepted premotor symptom, however, is that of sleep disorders, including RBD and hypersomnia, excessive sleepiness in the daytime; these are commonly reported by as many as 75% of PD patients, and frequently appear months or years prior to the development of motor symptoms (Adler, 2011; Iranzo, 2011). While evidence suggests that restless leg syndrome (RLS) is not a risk factor for developing PD, a similar sleep behavior, identifiable in overnight sleep studies, may also presage some cases of PD (Arnulf & Morgan, 2011). Recent studies of restlessness in legs that does not fit RLS diagnostic criteria has found that this is identified three times more frequently in early PD patients than in non-PD patients (Gjerstad, Tysnes & Larsen, 2011).

Interestingly, even after PD has been diagnosed, as often as 40% of the time patients do not declare their issues with hypersomnia, RBD, or insomnia, which can lead to compromised or inadequate treatment (Chaudhuri et al, 2012). Research by Chaudhuri et al. (2011) found that PD patients can be grouped into subgroups based on their sleep symptoms during either daytime or nighttime hours, which may also further support the concept of PD as a syndrome rather than a specific disease.

A European longitudinal study, Protective Validation of Risk Factors for the Development of Parkinson syndromes (PRIPS) has followed a baseline of 1847 adults at least 50 years, over a period of 3 years; the study is ongoing (Berg, 2012). This study has identified a combination of multiple markers (i.e., age >60, hyposomnia, UPDRS-III > 1, echotatus, etc.) that had as high as a 25% positive predictive value for development of PD within 3 years. However, the markers were present in less than 20% (2 of 11) of the participants who actually developed PD during that 3 year period (Berg, 2012) implying that though when present they had some predictive value, many other potential PD cases would not be detected by these markers. The author suggested longitudinal studies would benefit from using an enriched cohort of participants who are believed to have a substantial risk of developing PD, and following them to identify additional markers.

Berg (2011) also confirmed the difficulty of finding reliable premotor markers for PD, noting that to date, all known markers for PD had low predictive specificity, implying that relatively few patients with the marker ever develop PD, and the time between development of the marker and development of PD varied substantially from individual to individual (Berg, 2011). One of those markers is RBD, but Berg (2012) noted that only a subset of new PD patients exhibit RBD. Berg (2012) instead suggested that for those suspected of being at risk for development of PD, regular and frequent monitoring for even small loss of motor function may now be the best alternative for early diagnosis.

Early Parkinson’s Disease and Sleep

Sleep dysfunctions are typical of neurodegenerative diseases, probably due to the close integration between the regulators sleep in the hypothalamus and brainstem, which primarily integrate via reciprocal neural connections (Zhong, Naismith, Rogers, & Lewis, 2011). These same neural structures also are involved in cognitive behaviors, memory, and mood, so it is no surprise that dysfunction in these areas also correlate with dysfunction in sleep processes (Zhong et al., 2011). Typical sleep dysfunctions in any type of neurodegenerative disease includes disruption of the circadian system causing problems with the 24-hour sleep-wake cycle, dysfunction of the homeostatic system causing problems in falling or staying asleep , and disruptions of the ultraradian system causing problems with sleep stages (Zhong et al., 2011).

Another, possibly atypical, sleep-related disorder that has been reported in at least a few instances of PD is sleep related eating disorders (SRED) in which the patient experiences periodic episodes of binge eating and drinking during sleep (Sobreira-Neto, et al., 2011). In SRED, the food and drink consumed can be peculiar, highly unusual, or even toxic substances, and patients may experience damage from cutting or burning themselves during food preparation, since they are not fully conscious at the time the food is prepared and consumed (Sobriera-Neto et al., 2011). Such SRED is associated with sleepwalking, RLS, and with certain medications, including antidepressants, which might be used therapeutically with PD; in one reported case, the incidents of SRED behavior ceased after reducing the dosage of pramipexole taken for PD therapy (Sobriera-Neto et al., 2011). Thus, it seems clear that at least some cases of sleep dysfunction for PD patients may result from the pharmacological therapies used to treat the condition.

Approximately one-third to one-half of PD patients have been reported to exhibit RBD, which is associated with loss of skeletal muscle atonia during REM sleep and dream mentation (Yoritaka, Ohizumi, Tanaka & Hattori, 2009). Other studies cite the frequency of RBD at 20% to 65% (Zoccolella et al., 2011). Although RBD is not always associated with degenerative neurological disorders, in as many as 38% of patients 50 years or older, RBD patients eventually develop PD (Yoritaka et al., 2009). This is not a perfect correlation, however, since one-third to one-half of PD patients never experience RBD (Yorkitaka, et al., 2009). Yoritaka et al. (2009) found no significant differences that implied that PD medications were causal factors for RBD.

A very recent landmark study of 457 PD patients confirmed that 46% of the PD patients had validated RBD; similarly, the study showed strong associations with other neurodegenerative diseases such as certain types of dementia (Schenk & Boeve, 2011). The study based its RBD diagnoses solely on video-polysomnographic data rather than using anecdotal behavioral histories from patients, family, and caregivers (Schenk & Boeve, 2011).

Interestingly, in a review of studies of sleep disorder and PD, Zoccolella et al. (2011) noted that while in general population studies, sleep disorder incidence increased with the duration of the disease; in clinical studies, this relationship did not consistently hold. Factors that were associated with the development of sleep disorders in PD patients included older age, being male, using higher dosage dopaminergic treatments, cognitive impairments, and experiencing hallucinations (Zoccolella et al., 2011). In one study of Japanese population men, hypersomnia was also associated with three times the risk of developing PD (Zoccolella et al., 2011; Iranzo, 2011). Zoccolella et al. (2011) concluded that experiencing sleep disorders may be a premotor marker for development of PD or may be a risk factor for developing PD.

Tysnes, Muller, and Larsen (2010) also noted that autonomic and hypersomnic symptoms appear prior to motor symptoms in PD, and may herald early stages of PD. One proposed model is that PD symptoms begin in olfactory bulb, followed by affects in the autonomic innervation of both cardiac and digestive systems, and then by sensory dysfunction including pain and hypersomnia (Tysnes et al., 2010).

Bugalho, da Silva, and Neto (2011) also characterized RBD in early-stage PD, noting at what point the RBD symptoms appeared relative to PD onset, and when RBD symptoms occurred in non-RBD patients with respect to motor and cognitive dysfunctions. The study found frequent occurrence of RBD in the very early stages of PD, and even when symptoms fluctuated, physiopathological changes causing an association between PD and RBD may be constant despite such fluctuations (Bugalho et al, 2011).

Nirenberg (2011) noted that RBD is associated with abnormal cerebral perfusion patterns, and specifically also with impaired smell and color discrimination. This study noted that the pattern of cerebral perfusion with RBD patients resembled that of PD patients (Nirenberg, 2011). When the perfusion was reduced in the frontal and occipital regions, there was also a correlation to impaired color discrimination; when cerebral perfusion was reduced in the bilateral anterior hippocampal gyrus, there was a correlation with olfactory function (Nirenberg, 2011).

Identification of RBD technically requires an expensive, time-consuming video polysomnogram to identify the RBD symptoms of action-filled, vivid, and violent dreams characteristic of RBD (Nomura et al, 2011). A questionnaire form, the RBD screening questionnaire (RBDSQ) has been established which is more clinically practical and which can be used to identify RBD in patients (Nomura et al., 2011). PD patients who experienced violent RBD symptoms tended to score higher on the RBDSQ than those PD patients who did not have violent RBD symptoms (Nomura et al., 2011).

Amara et al. (2012) investigated the impact that one of the most effective PD treatments, that of unilateral subthalamic nucleus deep brain stimulation (STN DBS), has on sleep patterns for PD patients. These authors found that unilateral STN DBS improved the subjective sleep quality of the subjects, particularly when the STN DBS was performed on the right side of the brain (Amara et al., 2012).

Bugalho and Paiva (2011) investigated the issues of dream characteristics in early stage PD. Changes to dream characteristics may mirror PD development, beginning with vivid dreams, followed in sequence by hallucinations, and cognitive decline. Bugalho and Paiva (2011) studied the character of dreams in early-stage PD patients and found a pattern of changes to dreams in which there was increased aggression toward animals and increased presence of animals in dreams; these changes seemed related to increased frontal dysfunction.

A further connection between PD patients’ dream states and other nonmotor symptoms was cited by Manni et al. (2011), who noted that PD patients with RBD were more likely to experience visual hallucinations than those without RBD symptoms. This may be due to deficits in attentional, executive, visuoperceptual, and visuospatial skills, which are all associated with RBD (Manni et al., 2011).

Treatment of Early Stage PD

The evidence of premotor neuropathologies makes clear that PD involves the brainstem nuclei, the hypothalamus, the olfactory system, and peripheral autonomic nervous system. Because few clinical trials of nonmotor symptoms have been performed at this stage of PD, such premotor symptoms are often ignored and left untreated (Bhidayasiri & Truong, 2012). Even when PD therapies are begun, the emphasis is often exclusively on measurements of motor symptoms, ignoring other changes, including sleep disorders, cognitive changes, and olfactory and visual issues (Bhidayasiri & Truong, 2012).

Most PD treatment focuses on either pharmacological therapies or surgical treatments, generally such approaches provide measurable changes in motor symptoms (Uitti, 2012). However, such therapies have not improved much over the past several decades, while over the same time frame, the recognition of non-motor symptoms has grown including the issues of sleep dysfunction, cognitive dysfunction, and other issues (Uitti, 2012). These nonmotor symptoms are not only treatable, but also can have a tremendous impact on the patient’s quality of life (Uitti, 2012). Thus, addressing the mood and sleep disorders, and setting appropriate expectations along with establishing healthy routines may mitigate the decrease in functioning (Uitti, 2012).

An interesting, if brief, discussion of a randomized controlled study of using traditional Chinese herbs for sleep dysfunction in PD patients showed a remarkable improvement from disrupted sleep patterns to those indistinguishable from controls with neither PD nor sleep disruptions (Pan et al, 2011). In comparison, PD patients given a placebo showed no significant change or improvement in their impaired sleep patterns (Pan et al., 2011).

Conclusion

The most recognized sleep dysfunctions associated with PD are hypersomnia and RBD. Treatment with PD standard dopaminergic stimulation, in addition to assisting with nocturnal motor symptoms, also improves sleep quantity and quality in PD patients (Diederich & McIntyre, 2012). Other treatments for sleep dysfunctions in PD patients lack extensive clinical support due in part to the causal complexity of the relationship between PD and sleep dysfunctions (Diederich & McIntyre, 2012). Thus, the recommended treatments for such sleep dysfunctions in PD patients include multiple general strategies for sleep disorders (Diederich & McIntyre, 2012).

While the identification of early biomarkers for developing early stage PD is a major goal for researchers, Jones (2010) pointed out that such determinations are not necessarily useful to patients. At the moment, for example, if an early olfactory dysfunction leads to tests that confirm that a particular person is at risk for developing PD, there is no treatment or regimen known that can either slow or stop the progression of PD. Thus, the issue arises of whether such research will lead to improved patient outcomes, or merely to greater patient distress and worry over something that cannot be controlled or changed at the current time (Jones, 2010).

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