This article is the second in a series of three from the author on Parkinson’s disease.
In his “Essay on the Shaking Palsy,”1 James Parkinson described a condition with both motor and nonmotor aspects. Until recently, however, most attention was given to the motor aspects of the disease such as tremor and gait disturbance. This was reinforced in the 1960s with the advent of levodopa therapy.2 The innovation of augmenting brain dopamine levels with oral levodopa was an elegant demonstration that pharmacologic replacement of a depleted neurotransmitter could actually improve function. And motor function was indeed improved: tremor, rigidity, and bradykinesia all responded to this remarkable new therapy.
As treatment of motor symptoms continues to improve, with such added innovations as dopamine agonists and deep brain stimulation, it has become more obvious that myriad nonmotor symptoms such as depression, sleep disorders, and cognitive decline contribute not only to impaired function but to poor quality of life.3-5 Simultaneously, those studying the pathophysiology of the disease have expanded their focus from the events within the substantia nigra to other brain regions, the peripheral and autonomic nervous systems and areas such as the myenteric plexus and olfactory apparatus, where the disease may actually have its origin.6-8
This article will give a brief overview of some of the nonmotor features of Parkinson’s disease (PD), with some suggestions for management. The next article in the series will address another important category of nonmotor symptoms: neuropsychiatric manifestations such as dementia, depression, and hallucinations.
Persons with Parkinson’s disease experience a wide variety of problems with their sleep. Sleep architecture, already altered by aging, may be further disturbed as PD evolves to include brain regions such as the pedunculopontine nucleus, which is involved in the regulation of rapid eye movement (REM) sleep.9
Because of the brainstem involvement, one very common problem in PD is REM sleep behavior disorder (RSBD), in which patients act out their dreams instead of being paralyzed during them, as is normal. This is estimated to occur in up to 47% of persons with PD9 and is one of several nonmotor symptoms that may precede the motor aspects of the disorder.10,11 As with most sleep disturbances, this can be demonstrated during polysomnography. RSBD may be aggravated or precipitated by a variety of medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors.10 In the absence of complicating factors such as snoring or dementia, RSBD is often treated successfully with a small dose of clonazepam. If there is a suggestion of obstructive sleep apnea (OSA), also common in PD,12 this should be diagnosed and treated before sedating medications are prescribed.
One of the most commonly encountered sleep issues in PD is “wearing-off” of medication effect during the night, or even prior to sleep onset. This makes it difficult or even impossible to change position or adjust the bedclothes. Some patients describe waking up each morning in the exact same position in which they retired for the night, leading to complications produced by immobility, such as compression neuropathies or skin breakdown.
Sometimes, when the medication wears off, the patient is awakened by a sensation of uncomfortable warmth and experiences pronounced diaphoresis. When the medication effect wears off before bedtime, the patient may have difficulty getting comfortable enough to go to sleep and may even experience restless legs syndrome (RLS). Most of these problems can be addressed by adjusting the dopaminergic medication to cover these periods.
Depression is another common factor in parkinsonian sleep disturbance, often causing early morning awakening. This usually improves with treatment of the depression. Treatment of all parkinsonian sleep disturbances should include attention to good “sleep hygiene,” including keeping regular hours for sleeping and rising, and exposure to natural sunlight every day.
Daytime sleepiness is another frequent complaint in PD and is likely due to some of these sleep issues, as well as other factors such as medication side effects, variations in blood pressure, other medications, and medical conditions. Treatment with dopamine agonists is a frequent cause of daytime sleepiness.13 Sudden-onset sleep episodes may occur in PD patients; this may be related to factors such as daytime sleepiness and overall doses of dopaminergic medication.14
In addition to all of these factors, it is well known that many persons with PD experience fluctuations in their overall function from day to day. The quality of sleep may be one important factor in this variation.
Fatigue is an extremely common complaint of people with PD. It is a symptom not easily measured or quantified, often occurring in the absence of actual sleepiness. Fatigue may be associated with depression but also frequently occurs in the absence of depression, dementia, or sleep disturbance.15 In one study, fatigue was ranked as the most disabling symptom in one-third of patients. In the same study, fatigue did correlate strongly with depression.16
Gastrointestinal complaints occur often in PD and include dysphagia, nausea, and constipation.17 Constipation is one of several nonmotor complaints that may precede motor symptoms by years.18 Pathological studies have demonstrated Lewy bodies within the nerve fibers innervating the intestine.19 This is thought to be responsible for the slowing of movement within the colon, a problem compounded by other issues such as poor functioning of the muscles required for defecation, insufficient water intake, and medication side effects. Among the spectrum of nonmotor symptoms, constipation can be particularly distressing for the patient. In addition, build-up of fecal material may result in unnecessary exams ordered for abdominal or back pain and, if untreated, can result in emergency admissions for bowel obstructions. The best treatment for this is often multifactorial and includes increasing dietary fiber and water intake, promoting exercise, and the use of laxative medications. There is also a variety of nondrug remedies, including various recipes containing bran, prune juice, and senna teas. When used consistently, these can be very effective.
The involvement of the gastrointestinal tract may also cause symptoms in other regions including, frequently, the stomach.20 Delayed gastric emptying may result in early satiety, poor nutritional intake, and weight loss. The individual often describes sitting down to a meal with a good appetite but experiencing an uncomfortable sensation of fullness after only a few bites. Reflux disease is often another consequence of this slowness of gut transit time. Nausea may also be due to medications. When levodopa is converted to dopamine in the bloodstream, nausea is a frequent complaint. The addition of carbidopa to levodopa prevents this from occurring in most persons. Some, however, require additional carbidopa to block conversion. This can be ordered in the form of Lodosyn®, which contains only carbidopa.21 Other medications, such as domperidone and ondansetron, can also treat nausea in these patients when additional carbidopa is not effective, though domperidone is not available in the United States.21
Patients often complain of discomfort involving temperature regulation. As with so many other nonmotor symptoms, alterations in temperature perception may occur as a result of autonomic dysfunction.3 Many patients also experience a sensation of being overheated and diaphoretic as a symptom of wearing-off of dopaminergic medication effect. This frequently occurs during the night, when medication levels are at their lowest, and can usually be treated by adjusting the medications to last through the night using controlled-release carbidopa/levodopa or a long-acting dopamine agonist at bedtime.
Although PD is generally conceptualized as a motor disorder, pain is actually a frequent complaint. The patient often describes aching in limbs, often the shoulder, which may be due to the stiffness and rigidity that are part of PD and, as such, may be relieved by antiparkinsonian medications.3 Pain may also come as changes in posture aggravate degenerative conditions, such as spinal stenosis or cervical and lumbar radiculopathies.
It has become increasingly recognized that people with PD commonly lose the sense of smell. In fact, Lewy bodies have been found in the olfactory neurons.6 It has been suggested that PD may actually have its origin in these neurons or in those of the enteric nervous system.8
Orthostatic hypotension often occurs in PD because of the involvement of the autonomic nervous system, as well as antiparkinsonian medications. It may occur in up to 50% of patients and is more common in older patients taking large amounts of dopaminergic medication.22 In general, this is not a significant symptom until later in the disease. When blood pressure is measured sitting and standing, some degree of decline may be recorded, but the patient may not be symptomatic. When orthostatic hypotension is profound and occurs early in the disorder, this raises the possibility that the parkinsonism is due to multiple systems atrophy rather than idiopathic PD. Medications such as midodrine or fludrocortisone may be helpful, though they may cause dangerous elevations in supine blood pressure. Therefore, close monitoring of supine and standing blood pressures is warranted. Pyridostigmine has been successfully used to treat some patients with neurogenic orthostatic hypotension and may be less likely to cause supine hypertension.23 Other measures, such as attention to fluid and salt intake, sleeping with the head of the bed elevated, and eating multiple small meals to avoid diverting large amounts of blood to the GI tract, should also be implemented.
Persons with PD can present with skin changes in several forms. Drug rashes can occur from amantadine and may give the lower extremities a red and mottled appearance, often accompanied by edema. This is called livedo reticularis and usually resolves when amantadine is discontinued. Occasionally, a patient will have a macular rash from levodopa therapy. This is usually due to the yellow tartrazine dye in the 25/100 strength and resolves when the prescription is changed to 10/100, which is blue.24,25
The skin changes caused by PD itself most commonly take the shape of seborrheic dermatitis, resulting in redness and flaking of patchy areas of skin.26 When this occurs around the eyes, the flakes may involve the eyelashes and get into the eyes, which can be very irritating for the patient. Sometimes, this responds to the use of a dandruff shampoo, allowed to run over the face (with the eyes closed) or a corticosteroid cream.
There is some evidence that persons with PD also have a slightly higher incidence of melanoma.27 The possible role of dopaminergic medications in promoting this increase is under study.
Because the pathophysiology of PD often involves the autonomic nervous system, bladder function may be affected. The most common abnormality is detrussor hyperreflexia, which leads to symptoms of urgency and frequency.28 Frank incontinence is unusual, but many patients develop urge incontinence, as they are not aware of the bladder filling up until the need to void is acute. At this point, the stress of getting to the bathroom further hampers mobility and makes getting there in a timely manner more difficult. Sometimes, asking a patient to void more frequently, without waiting for a sensation of bladder fullness, will decrease the likelihood of accidents and the anxiety that they provoke.
Sexual function in PD may be altered in several ways. Alterations in the autonomic nervous system may affect the ability to maintain an erection in men.29 Women with PD may also experience sexual dysfunction.30 Treatment with sildenafil may be helpful in men,29 and patients have described improvements with similar agents as well. There is a paucity of information on the treatment of sexual issues in women with PD.
Medications for depression or other conditions may also alter sexual function. Depression and other cognitive changes may affect interpersonal relationships and alter sex drive. In addition, some antiparkinsonian medication may produce compulsive behaviors such as an unusual interest in sex in a small number of patients.31 When this happens in the context of cognitive impairment or a relationship where sexual activity has been absent for many years, it can be very disturbing for both persons.
Even in early PD, patients exhibit worsening of visual acuity, as compared with elderly control subjects. Visual perception was also worse in the PD group.32 The authors of this study describe defects occurring at the level of the retina, subcortex, and cortex. They also suggest that testing visual function early in PD and following the progression of these findings may give important information about disability in persons with PD, especially those with cognitive dysfunction.
In advancing PD, patients often complain of diplopia or intermittent blurring of vision,33 especially when switching from near to distant vision. In some cases, the diplopia is due to a convergence insufficiency that responds to levodopa.34
When the diplopia does not respond to adjustments in medication, but is consistently present in one direction, an ophthalmologist may be able to fit the patient’s glasses with prisms to correct the defect. Defects that are inconsistent and do not respond to levodopa are not easily treated.
Occasionally, patients with parkinsonian conditions also experience involuntary closure of the eyelids. This may represent apraxia of the eyelid opening, which is failure of the reflex tendency to keep the eyes open when awake, or blepharospasm, a dystonic closure of the eyelids.
Identification and treatment of the nonmotor aspects of PD are extremely important for attaining the best possible quality of life in this patient population. In addition, it is becoming apparent that the pathogenesis of these symptoms may provide important clues about the way PD evolves within the brain and body.
The author reports no relevant financial relationships.