Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. At this time, PD can be slowed with treatment but not halted. Estimates suggest that about 50,000 Americans are diagnosed with PD each year, although some estimates are much higher. PD affects about 50 percent more men than women.
Advancing age is a clear risk factor for PD. The average onset is 60 years, and the incidence rises significantly the older a person becomes. Nevertheless, about 5 to 10 percent of people with PD have “early-onset” disease that begins before the age of 50. Most of early-onset cases are linked to specific gene mutations. An estimated 15 to 25 percent of people with PD have a known relative with the disease. In some rare cases, PD may appear in people before the age of 20 years; this condition is called juvenile Parkinsonism.
Pathogeneses
Parkinson’s disease is a motor systems disorder that occurs when neurons in the brain die or become impaired. Although many brain areas are affected, the most common symptoms result from a progressive deterioration of neurons in an area near the base of the brain called the substantia nigra. Normally, these neurons produce dopamine. Dopamine is a chemical messenger responsible for transmitting signals between the substantia nigra and the corpus striatum, to produce smooth, purposeful muscle movement. Loss of dopamine results in abnormal nerve impulse patterns within the brain that cause diminished movement.
Studies have shown that most people with Parkinson’s have lost 60 to 80 percent or more of the dopamine-producing cells in the substantia nigra by the time symptoms appear. People with PD also have loss of the nerve endings that produce norepinephrine. Norepinephrine, which is closely related to dopamine, is the main chemical messenger of the sympathetic nervous system. The sympathetic nervous system controls many automatic functions of the body, such as pulse and blood pressure. The loss of norepinephrine might explain several of the non-motor features seen in PD, including fatigue and abnormalities of blood pressure regulation.
Several genes have been definitively linked to PD. The first to be identified was alpha-synuclein. In the 1990’s, researchers at National Institutes of Health and other institutions studied the genetic profiles of a large Italian family and three Greek families with familial PD and found that their disease was related to a mutation in this gene. They found a second alpha-synuclein mutation in a German family with PD. These findings prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies (protein deposits) seen in all cases of PD contain alpha-synuclein protein. This discovery revealed the link between hereditary and sporadic forms of the disease. Researchers do not yet know why Lewy bodies form or what role they play in the disease, though some speculate that the protein buildup in Lewy bodies is part of an unsuccessful attempt to protect the cell from the toxicity of synuclein. There are several other gene mutations that have been linked to PD, some with regional clusters. LRRK2 mutations are a major cause of PD in North Africa and the Middle East.
Environmental causes
There is some evidence that certain environmental factors or toxins cause Parkinson’s disease. Scientists have suggested that external or internal toxins may selectively destroy the dopaminergic neurons, causing Parkinson’s disease. Toxins that may be linked to Parkinson’s include manganese, carbon monoxide, carbon disulfide, and some other pesticides. Another thought is that oxidized free radicals produced by toxins may lead to PD. These free radicals are believed to damage tissue and specifically neurons. More research as to the use of pesticide and the environmental causes of PD is ongoing. The chemical MPTP also causes a permanent unresponsive form of Parkinsonism that closely resembles PD. Investigators discovered this reaction in the 1980s when heroin addicts in California who had taken a street drug contaminated with MPTP began to develop severe Parkinsonism. This discovery showed that a toxic substance could damage the brain and produce parkinsonian symptoms, and led to dramatic breakthroughs in Parkinson’s research.
Symptoms
Early symptoms of PD are subtle and usually occur gradually. In some people, the disease progresses more quickly than in others, though PD appears to progress slower with early diagnosis and treatment.
The four primary symptoms of PD are tremors, rigidity, bradykinesia, and postural instability:
The tremor associated with PD has a characteristic appearance. Typically, the tremor takes the form of a rhythmic back-and-forth motion at a rate of 4-6 beats per second. It may involve the thumb and forefinger and appear as a “pill rolling” tremor. Tremors often begin in a hand, although sometimes a foot, cheek, jaw and lip is affected first. Initially, the tremor is unilateral. It is most obvious when the hand is at rest or when a person is under stress. Tremors usually disappears during sleep or improve with intentional movement. It is usually the first symptom that causes people to seek medical attention.
Rigidity or a resistance to movement affects most people with PD. The muscles remain jumpy and contracted so that the person aches or feels stiff. This stiffness does not go away with exercise and can affect hip and shoulder joints. The rigidity is increased when an extremity is passively moved. This jerky motion is called “cogwheel” rigidity. PD patients often develop a so-called parkinsonian gait that includes a tendency to lean forward, taking small quick steps as if hurrying (called festination), and reduced swinging in one or both arms. They may have trouble initiating movement (start hesitation), and they may stop suddenly as they walk (freezing).
Slowed movements or bradykinesia is often associated with an impaired ability to adjust the body’s or muscle position. This symptom makes even routine tasks difficult. Facial expressions may also slow giving a “masked” appearance to facial features. Frequently people appear to have a “blank stare” and blinking is decreased.
Postural instability, or impaired balance, causes affected individuals to fall easily. Orthostatic hypotension is a sudden drop in blood pressure when a person stands up from a lying-down or seated position. This may cause dizziness, lightheadedness and, in extreme cases, loss of balance or fainting. This is a result of decreases in the sympathetic nervous system that regulate homeostasis.
A number of other symptoms may accompany PD, and some can be treated with medication or physical therapy.
Depression may be seen even before the diagnosis of PD. This common disorder may appear early in the course of the disease, even before other symptoms are noticed. Other behavioral symptoms are becoming fearful, irritable and insecure.
Swallowing and chewing difficulties that increases with the advancement of the disease leading to an increase risk of aspiration and poor dietary intake.
Speech changes occur in half of all individuals with PD. This may be characterized as speaking too softly, in a raspy, hoarse manner or in a monotone.
Urinary problems or constipation may be seen due to the improper functioning of the autonomic nervous system, which is responsible for regulating smooth muscle activity.
Changes in skin type may occur particularly on the forehead and at the sides of the nose. It may become oily or dry. The scalp may develop dandruff.
Sleep problems are common in PD and include difficulty staying asleep at night, restless sleep, nightmares, emotional dreams, and drowsiness or sudden sleep onset during the day. “REM behavior disorder,” in which people act out their dreams, potentially resulting in injury to themselves or their bed partners has been seen. Medications used to treat PD may contribute to some of these sleep issues.
Cognitive problems become more severe in late stages of PD, and a diagnosis of Parkinson’s disease dementia (PDD) may be given. Memory, social judgment, language, reasoning, or other mental skills may be affected. There is currently no way to halt PD dementia, but some drugs may help. The medications used to treat the motor symptoms of PD may cause confusion and hallucinations.
Fatigue, especially late in the day is common. Fatigue may be associated with depression or sleep disorders, but it may also result from muscle stress. Fatigue may also result from akinesia—trouble initiating or carrying out movement. Exercise, good sleep habits, staying mentally active, and not forcing too many activities in a short time may help to alleviate fatigue.
PD may cause sexual dysfunction due to changes in neuron signals. PD related depression or use of certain medications may also cause decreased sex drive.
Loss of the sense of smell is an early and progressive symptom that can lead to nutritional challenges.
As the disease progresses, the symptoms of Parkinson’s disease may begin to interfere with daily activities. Affected individuals may not be able to hold utensils steady or shave themselves. People with PD may have some or all of these symptoms.
Differential Diagnosis
A number of disorders can cause symptoms similar to those of PD. People with symptoms that resemble PD but that result from other causes are considered to have Parkinsonism. Some of these disorders include:
Multiple system atrophy.
Dementia with Lewy bodies
Progressive supranuclear palsy
Corticobasal degeneration.
Arteriosclerotic Parkinsonism. Sometimes known as pseudoparkinsonism, involves damage to the brain due to multiple cerebral vascular events. Tremor is rare in this type of Parkinsonism, while dementia and difficulties with gait are common. Antiparkinsonian drugs are of little help to people with this form of Parkinsonism.
Post-traumatic Parkinsonism. Also known as post-traumatic encephalopathy, these parkinsonian symptoms can develop after a severe head injury or repeated head trauma.
Normal pressure hydrocephalus. Normal pressure hydrocephalus (NPH) is an abnormal increase of cerebrospinal fluid (CSF) in the brain’s ventricles. Many symptoms mimic that of PD. They do not respond to Parkinson’s medications.
Parkinsonism accompanying other conditions. Parkinsonian symptoms appear in individuals with other, clearly distinct neurological disorders such as Wilson’s disease, Huntington’s disease, Alzheimer’s disease, spinocerebellar ataxias, or Creutzfeldt-Jakob disease. Each of these disorders has specific features that help to distinguish it from PD.
Postencephalitic Parkinsonism. After World War I, viral encephalitis infected almost 5 million people and then suddenly disappeared in the 1920s. Also known as sleeping sickness, this disease killed one-third of its victims and led to post-encephalitic Parkinsonism in many others. Symptoms appeared sometimes years after the initial illness. In 1973, neurologist Oliver Sacks published Awakenings, an account of his work with those surviving post-encephalitic illness. His use of the drug levodopa was able to temporarily “awaken” these individuals and was instrumental in the treatment of PD. Other viral infection encephalopathies have caused parkinsonian symptoms.
Drug-induced PD – A reversible form of PD is sometimes the results of use of certain drugs, such as chlorpromazine, haloperidol, or reserpine which are typically prescribed for patients with psychiatric disorders. Drugs such as metoclopramide and others such as valproate can cause tremor and bradykinesia. Stopping the medication usually causes the symptoms to disappear
Diagnosis
There are currently no blood or laboratory tests that diagnose PD. Therefore, the diagnosis is based on medical history and a neurological examination. This exam is monitored over time for its severity and progression of symptoms. Providers may sometimes request brain scans or laboratory tests in order to rule out other disorders. Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal, but they are essential to rule out other diseases and insure proper care. There are new photon emission computed tomography (SPECT) methods that may be used as choice for differentiation between neurodegenerative and non-neurodegenerative Parkinsonism. A new PET method provides a very high diagnostic accuracy for differentiating between Parkinson’s disease and atypical Parkinsonian syndromes, though it is not definitive of PD.
Treatments
Medications for PD fall into three categories. The most common drugs for PD are dopamine-precursor substances such as levodopa that cross the blood-brain barrier. These drugs then are changed into dopamine once in the body. The second are PD drugs affect other neurotransmitters in the body in order to ease some of the symptoms of the disease. Anticholinergic drugs interfere with the production or uptake of the neurotransmitter acetylcholine.
The third category of drugs prescribed for PD includes medications that help control the non-motor symptoms of the disease; that is, the symptoms that don’t affect movement.
Levodopa/Carbidopa – The cornerstone of therapy for PD is the drug levodopa (also called L-dopa). Nerve cells can use levodopa to make dopamine and replenish the brain’s reduced supply. People cannot simply take dopamine pills because dopamine does not easily pass through the blood-brain barrier. Usually, people are given levodopa combined with carbidopa. When added to levodopa, carbidopa prevents the conversion of levodopa into dopamine except for in the brain; this stops or diminishes the side effects due to dopamine in the bloodstream. Nerve cells can use levodopa to make dopamine and replenish the brain’s dwindling supply. Although levodopa helps at least three-quarters of parkinsonian cases, not all symptoms respond equally to the drug. Levodopa/carbidopa are often very successful at reducing or eliminating the tremors and other motor symptoms. Dosages may need to be increased to maximize benefit. Although they can reduce the symptoms of PD, these medicines do not replace lost nerve cells and they does not stop the progression of the disease.
Levodopa/carbidopa can have a variety of side effects. The most common initial side effects include nausea, low blood pressure, and restlessness. The drug also can cause drowsiness or sudden sleep onset, which can make driving and other activities dangerous. Long-term use of levodopa sometimes causes hallucinations and psychosis. These drugs may be taken with or without food, but appear to be better tolerated with food in some patients. The medication is usually taken 3-4 times a day and timing of dosage is important to prevent off periods of therapy.
In March 2017, the FDA approved safinamide tablets as an add-on treatment for individuals with PD who are currently taking levodopa/carbidopa and experiencing “off” episodes (when the person’s medications are not working well), which cause an increase in PD symptoms. Side effects are similar to that of levodopa. This drug should not be taken in people with liver conditions or who are taking other MAO inhibitors.
Dopamine Agonists – These drugs, which include apomorphine, pramipexole, ropinirole, and rotigotine, mimic the role of dopamine in the brain. They can be given alone or with levodopa. They are somewhat less effective than levodopa in treating PD symptoms, but work for longer periods of time. Many of the potential side effects are similar to those associated with the use of levodopa, including drowsiness, sudden sleep onset, hallucinations, confusion, dyskinesias, edema, nightmares, and vomiting. In rare cases, they can cause decreased inhibition, which may in turn cause an uncontrollable desire to gamble, hypersexuality, or compulsive shopping.
MAO-B inhibitors -These drugs inhibit the enzyme monoamine oxidase B, or MAO-B, which breaks down dopamine in the brain. MAO-B inhibitors cause dopamine to accumulate in surviving nerve cells and reduce the symptoms of PD. Studies supported by the NINDS have shown that selegiline (also called deprenyl) can delay the need for levodopa therapy by up to a year or more. When selegiline is given with levodopa, it appears to enhance and prolong the response to levodopa and thus may reduce “wearing-off.” Selegiline is usually well-tolerated, although side effects may include nausea, orthostatic hypotension, or insomnia. It should not be taken with certain antidepressants, meperidine, or St John’s Wart since combination can cause confusion, hypertension, coma and death.
COMT inhibitors – COMT stands for catechol-O-methyltransferase, another enzyme that breaks down dopamine. The drug entacapone and tolcapone prolong the effects of levodopa by preventing the breakdown of dopamine. COMT inhibitors can decrease the duration of “off periods” of one’s dose of levodopa. The most common side effect is diarrhea. The drugs cause nausea, sleep disturbances, dizziness, urine discoloration, abdominal pain, low blood pressure, or hallucinations. In a few rare cases, tolcapone has caused severe liver disease, and people taking tolcapone need regular monitoring of their liver function.
Amantadine – This antiviral drug can help reduce symptoms of PD and levodopa-induced dyskinesia. It is often used alone in the early stages of the disease. It may also be used with an anticholinergic drug or levodopa. After several months, amantadine’s effectiveness wears off in up to half of the people taking it. Amantadine’s side effects may include insomnia, mottled skin, edema, agitation, or mood changes.
Anticholinergics – These are used to decrease the activity of the neurotransmitter acetylcholine and can be particularly effective for tremor. Side effects may include dry mouth, constipation, urinary retention, hallucinations, memory loss, blurred vision, and confusion.
When recommending a course of treatment, a provider will assess how much the symptoms disrupt the person’s life and then tailor therapy to the person’s particular condition. Since no two people will react the same way to a given drug, it may take time and patience to get the maximum benefit.
Deep Brain Stimulation
The earliest types of surgery for PD involved selectively destroying specific parts of the brain that contribute to PD symptoms. The most common surgery was pallidotomy. In this procedure, a surgeon selectively destroys a portion of the brain called the Globus pallidus. Pallidotomy can improve symptoms of tremor, rigidity, and bradykinesia. Some studies have also found that pallidotomy can improve gait and balance and reduce the amount of levodopa people require. Another procedure, called thalamotomy, involves surgically destroying part of the thalamus, this approach is useful primarily to reduce tremor but is not usually done as often as new techniques.
Because these procedures cause permanent destruction of small amounts of brain tissue, they have largely been replaced by deep brain stimulation. However, a new method using focused ultrasound waves from outside the head is being tested because it creates lesions without the need for surgery.
Deep brain stimulation (DBS), uses an electrode surgically implanted into part of the brain, typically the subthalamic nucleus or the globus pallidus. When turned on using an external wand, the pulse generator and electrodes painlessly stimulate the brain in a way that helps to block signals that cause many of the motor symptoms of PD. DBS is approved by the U.S. Food and Drug Administration and is widely used as a treatment for PD. This treatment is shown to reduce tremors, bradykinesia and rigidity. Stimulation of the thalamus is useful primarily for reducing tremors. This treatment is less helpful with speech, balance, depression and dementia issues. Frequent monitoring of the stimulator is required with the battery life of up to five years before it needs replacing.
DBS does not stop PD from progressing, and some problems may return. This device is generally appropriate for people with levodopa-responsive PD. As with any brain surgery, DBS has potential complications, including stroke, infection or brain hemorrhage.
Diet
At this time, there are no specific vitamins, minerals, or other nutrients that have any proven therapeutic value in PD. An NINDS clinical study of the dietary supplement coenzyme Q10 was stopped in 2011 when results from an analysis showed active treatment with this supplement was unlikely to demonstrate a statistically significant difference than that of a placebo. The National Institutes of Health are funding research to determine if caffeine, antioxidants, and other dietary factors may be beneficial for preventing or treating PD. That being said, some dietary methods may help reduce the symptoms of PD. Eating a fiber-rich diet and drinking plenty of fluids can help alleviate constipation. A high protein diet, however, may limit levodopa’s absorption, stressing the importance of the timing of medications.
Exercise
The effects of exercise on disease progression are not known, but it may improve body strength and balance by minimizing gait problems. Occupational therapy can strengthen muscles so that people can speak and swallow better, thereby decreasing their risk of aspiration. Techniques in speech therapy can help with the low talking volume seen in PD patients. An NINDS-funded clinical trial demonstrated the benefit of tai chi exercise compared to resistance or stretching exercises. Other complementary and supportive therapies that are used by some individuals with PD include massage therapy, yoga, hypnosis, acupuncture, and the Alexander technique, which optimizes posture and muscle activity.
Prognosis
Parkinson’s disease affects people in individual ways, but it commonly appears to have five different stages. The time spent at each stage varies, and the skipping of stages is not uncommon.
Hoehn and Yahr Staging of Parkinson’s Disease
- Stage one
- Tremor and extremity shaking on one side of the body only. Family and close friends may notice changes in facial expressions.
- Stage two
- Bilateral symptoms. No consistent impairment of balance. Increasing difficulty with activities of daily living.
- Stage three
- Balance impairment. Mild to moderate disease. Physically independent but may require assistance. Noticeable slowing of physical movements.
- Stage four
- Severe disability, but still able to walk or stand unassisted. Day to day activities require assistance. Occasionally tremors will decrease during this stage.
- Stage five
- Wheelchair-bound or bedridden. This stage requires continual care for all activities.
Another commonly used scale is the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). This four-part scale measures motor movement along with non-motor experiences of daily living, motor experiences of daily living, motor examination, and motor complications to determine prognosis. As the disease progresses, the need for frequent assessment of fall and aspiration risk increases. Preventive patient safety measures are of primary nursing concern.
PD is both chronic and progressive. Although some people become severely disabled, others experience only minor motor disruptions. Tremor is the major symptom for most individuals, while for others tremor is only a minor complaint and other symptoms are more troublesome. It is currently not possible to predict which symptoms will affect an individual, and the intensity of the symptoms also varies from person to person. Due to the prominence of certain celebrities such as Michael J. Fox and Mohammad Ali, PD has received increased funding and awareness; hopefully these effects will lead to more effective treatment and potentially a cure.
References:
Brabenec L, Mekyska J, Galaz Z, and Rektorova I. (2017). Speech disorders in Parkinson’s disease: early diagnostics and effects of medication and brain stimulation. J Neural Transm (Vienna), 124 (3), 303-344. Retrieved from https://www.clinicalkey.com/#!/content/medline/2-s2.0-28101650.
FDA approves drug to treat Parkinson’s disease. (2017). FDA. Retrieved from https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm547852.htm.
Meyer PT, Armtage F, and Hellwig, S. (2014). Differential diagnostics of Parkinson’s disease with nuclear medicine procedures. Nervenartz, 85 (6), 680-689. Retrieved from https://www.clinicalkey.com/#!/content/medline/2-s2.0-24821290.
Parkinson’s Disease Information Page. Retrieved from https://www.ninds.nih.gov/disorders/all-disorders/parkinsons-disease-inf…
Parkinson’s Disease: Hope Through Research. (2018). Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Thr…
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