Parkinson’s Disease Associated Sleep Disorders - Novel Treatments

What is Cognitive Impairment?

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–2% of the population over the age of 65. It presents with the following motor symptoms: tremor at rest; difficulty walking, getting in and out of a chair, and turning; muscle stiffness; change in facial expressions; smaller handwriting; and many others. Nonmotor symptoms are also common and include constipation, loss of smell, orthostatic hypotension, fatigue, depression, anxiety, and—in particular—sleep abnormalities. Insomnia is fairly common in general population and especially in the elderly; however, there are some unique features associated with PD sleep changes.

Sleep Abnormalities in PD

In addition to difficulty falling asleep and staying asleep, patients with PD suffer from frequent waking, which results in fragmented sleep and inability to progress from light into deep sleep. Deep sleep (stages 3–4 of the sleep cycle) is critical to memory consolidation, proper immune function, metabolism regulation, and hormone secretions. Sleep efficiency, which is defined as the amount of time spent asleep versus total amount of time spent in bed, is also reduced and may be contributing to excessive daytime sleepiness which is frequently seen in PD. Other abnormalities include Restless Leg Syndrome, the uncomfortable sensation that forces the patient to keep moving their legs at night, and Rapid Eye Movement (REM) Sleep Behaviour Disorder. During healthy REM sleep the muscles are in a state of relaxation, with almost complete loss of muscle tone, while the eyes and the brain are very active. The eyes move rapidly as if watching a dream, while the brain is thought to process emotions and memories from the day’s experience. In patients with PD, this time is characterized by a loss of physical relaxation, resulting in the following behaviours: talking, hitting, punching, shouting, or even getting up and walking during sleep. Not only does this place the patient at risk of harm during the night, but it may also interfere with increased dopamine production that typically occurs during sleep, adding fuel to the fire of this condition.

Factors Influencing Sleep in PD

The main treatment for PD is levodopa, a synthetic form of dopamine. It has been shown to produce mixed effects on sleep. On the one hand it helps with nocturnal akinesia, which is the inability to move or moving with great difficulty at night (e.g. getting up to use the restroom or rolling over in bed), but on the other hand it reduces the overall duration of REM sleep and delays its onset. REM sleep is important, as during this time the blood flow to the brain increases, and there is an increase in neurotransmitter production and replenishment, such as dopamine. Furthermore, decrease in REM sleep has been associated with increased daytime sleepiness, which further negatively impacts activities of daily living and interferes with quality sleep at night.

Recent research suggests that light deprivation may be in part responsible for the sleep abnormalities that are part of the pathology of PD. Light is used by the body as a regulator of the circadian rhythm that governs sleep and wakefulness. It is generated by the hypothalamus, specifically the suprachiasmatic nucleus, and is also important in regulating temperature, energy metabolism, hormone secretion, and many other factors. In healthy patients, we typically see a spike in cortisol in the morning, and a spike in melatonin at night when it is dark, as light exposure suppresses melatonin production within the pineal gland. Dysregulation of this rhythm has been associated with weight gain, mood changes (both anxiety and depression), as well as some digestive disorders like irritable bowel syndrome (IBS). In the case of patients with PD, this rhythm appears to be blunted or lost, with a reduced spike in morning cortisol and a reduced spike in nightly melatonin. The lack of light exposure is believed to be due to structural changes of the eye, resulting in less light reaching the photoreceptors (e.g. cataract development) and as a result of lifestyle factors—less time spent outdoors for fear of falling because of balance issues, or difficulty walking (especially in the winter!). Without adequate and timely light exposure, the suprachiasmatic nucleus is deprived of its usual trigger for rhythm generation, resulting in circadian rhythm abnormalities.

Novel Treatment

Bright light therapy has been fairly well established as a successful treatment in seasonal affective disorder and depression, with results comparable to standard pharmaceutical options and psychotherapy. In 2008 it was demonstrated to slow down the cognitive decline seen in patients with dementia, and in 2011 to improve sleep and reestablish healthy circadian rhythm patterns in elderly patients with depression.

Several studies explored the role of bright light therapy (BLT) on patients with PD and yielded favourable results. A case series of 12 patients demonstrated significant improvement in insomnia and depressive symptoms. The light was delivered using a BLT machine that produced 1,000–1,500 lux for 60–90 minutes just before bedtime for a duration of 2–5 weeks. A lux is a unit of luminous emittance; in other words, light intensity or degree of brightness. For example, typical office lighting provides between 300 and 500 lux, while daylight and surgical rooms deliver 10,000 lux. The improvement in sleep was short-lived—only lasting for a few days after discontinuation of the BLT—but the antidepressant effects lasted for several weeks. However, the most striking improvement was in the motor symptoms of PD, specifically the bradykinesia (slowing down and difficulty initiating movement) and rigidity (increased muscle tension). The degree of effect varied significantly between patients, with younger patients receiving more significant benefit from this therapy. It is important to add that the improvement was significant enough to allow the patients the opportunity to reduce their dopamine medications, in one case by as much as 100%.

A small (18 participants) randomized control trial comparing light exposure of 7,500 lux versus 950 lux for 30 minutes a day (morning) for two weeks demonstrated significant improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) section 1, and mild improvement in tremor with higher light intensity. The UPDRS 1 evaluates cognitive function, such as memory and problem-solving skills, presence of hallucinations, and signs of depression and loss of motivation. Interestingly, there was minimal improvement in sleep, which may be explained by the short duration of the exposure (only 30 minutes) or the timing of the BLT (morning versus before bedtime). No motor changes were observed in this study. Another observation study on BLT in PD reports using higher-intensity light of 4,000–6,000 lux for 60 minutes before bed for a few months compared to a few years. The participants that used the light therapy for years demonstrated significant improvement in motor symptoms, such as bradykinesia, balance impairment, and rigidity. In comparison to the participants who stopped after a few months, the light therapy appeared to delay the progression of the disease and interfere with the severity of the motor decline. Additional benefits included changes in anxiety and depression.

Treatment Safety

While the studies are quite promising, there is little agreement on the specifics of the bright light therapy protocol. Questions remain regarding dose (e.g. light intensity), duration of exposure (e.g. 30 or 60 min), and time during the day (e.g. morning or evening). Known side effects seen with BLT include headaches, eye strain, vision problems, and nausea. The main drug interaction of concern is with medications that sensitize the skin to light; these include tricyclic antidepressants, St. John’s wort, antiarrhythmic medications, and tetracyclic antibiotics. Patients who suffer from conditions that are aggravated by light exposure—such as systemic lupus erythematosus, porphyria, actinic dermatitis, retinal dystrophy, macular degeneration, and solar urticaria—should be monitored by dermatologists and ophthalmologists.

Conclusion

Patients with PD frequently suffer from sleep abnormalities that not only further challenge their quality of life, but also contribute to the progression of the disease, as they interfere with the restorative functions of normal sleep. The changes are believed to be part of the pathogenic process of the condition, as dopamine is part of sleep-cycle regulation and awakening. Medications that are typically used in managing symptoms may be contributing as a double-edge sword—both improving sleep quality by ameliorating nightly movement abnormalities, but at the same time reducing REM sleep. In addition, lack of sunlight exposure, due to lifestyle factors and vision changes, may be responsible for these changes in sleep patterns. Bright light therapy has been demonstrated to improve mood and sleep. In several small studies with patients with PD, light therapy has demonstrated the ability to interfere with motor symptoms, including bradykinesia, tremor, and rigidity. While further research is required to develop the most safe and effective protocol for bright light therapy and to explore its full impact on PD symptoms, the initial results offer some hope at finding a therapy that may slow down the progression and offer a safe alternative to dopamine-replacement therapies.