Treatment Options
At this time no treatment has been shown to slow or stop the progression of this disease. Instead, therapy is directed at treating the symptoms that are most bothersome to an individual with Parkinson's disease. For this reason, there is no standard or “best” treatment for Parkinson's disease. Treatment approaches include medication and surgical therapy. Other treatment approaches, including general lifestyle modifications (rest and exercise), physical therapy, speech therapy, will be covered in Maintaining Optimal Wellness.
Medications for Parkinson's disease
Because individuals with PD have a range of symptoms, the choice of medication (and the decision whether to treat with medication) varies considerably between individuals. Moreover, over time, the dose of medications may need to be increased or new medications added.
Commonly Prescribed Medications
Levodopa is modified by brain enzymes to produce dopamine. The introduction of levodopa (or L-dopa) treatment more than 30 years ago revolutionized treatment of Parkinson's disease. For most individuals, it reduces the symptoms of slowness, stiffness and tremor and to date remains the most effective treatment for many of the symptoms of Parkinson's disease. Since blood enzymes (called AADCs) would break down most of the levodopa before it reached the brain, it is always combined with an enzyme inhibitor called carbidopa (or benserazide in Europe).
After being absorbed in the gastrointestinal tract, levodopa is transported to the brain, where it is converted into dopamine. It is subsequently released by brain cells and activates dopamine receptors allowing for normal function of the movement control centers of the brain.
Levodopa is available as a standard (or immediate) release formulation or a long-acting or “controlled-release” formulation. Controlled release may provide a longer duration of action by increasing the time it takes for the gastrointestinal tract to absorb levodopa.
Over the years, a number of substitutes for levodopa have been developed. Unlike levodopa, these medications do not have to be modified by brain enzymes in order to activate dopamine receptors. As a class, these medications are called dopamine agonists and may be used in place of levodopa or in combination with it. Although dopamine agonists appear to cause motor fluctuations less frequently than levodopa, dopamine agonists are more likely to cause other side effects than levodopa, so physicians must consider a number of factors in deciding which medication to recommend. The various dopamine agonists differ in several respects, including chemical structure, duration of action, and side effects. The response to a particular dopamine agonist varies considerably between individuals, so that if one dopamine agonist does not offer benefit or causes bothersome side effects, another agonist may be tried.
A number of other medications can be used alone or in combination with levodopa or a dopamine agonist to improve movement for people with PD. These medications do not stimulate dopamine receptors but alter the movement control center by other means. The most commonly used medications are amantadine, anticholinergic medications, and selegiline.
Amantadine was initially developed as an antiviral medication. By coincidence it was found to help the symptoms of Parkinson's disease. It may be used alone or in combination with levodopa or dopamine agonists. Amantadine reduces symptoms of fatigue, tremor and bradykinesia in some people with early Parkinson's disease. For people with more advanced PD, amantadine may reduce motor fluctuations, in particular, dyskinesias.
Anticholinergic medications are the oldest class of medications available for Parkinson's disease. Anticholinergic medications may reduce tremor or rigidity. They can be taken alone or in combination with levodopa. These drugs are rarely used in elderly patients or those with cognitive problems, because increased confusion can be one of their side effects.
Selegiline is an inhibitor of the enzyme MAO-B (monoamine oxidase B). Since this enzyme breaks down dopamine, inhibiting it prolongs the action of dopamine in the brain, and may improve the symptoms of Parkinson's disease. It also has a mild antidepressant effect. Although early studies of selegiline initially led physicians to believe that it may delay the progression of Parkinson's disease, currently there is no firm evidence that this is so.
List of Commonly Prescribed Medications
(Generic Name and Product Name)
In this section, we provide the names of commercially available preparations and a brief account of some of the more common side effects. The list of side effects is not complete, and patients should consult their physician if these or other ill-effects develop while they are taking any of these medications.
Levodopa preparations:
Standard release preparations:
- levodopa/carbidopa (Sinemet® or Atamet®)
- levodopa/benserazide (Madopar®--not available in the United States)
Extended release preparations:
- levodopa/carbiopa (Sinemet CR®)
- levodopa/benserazide (Madopar HBS®)
Side effects include nausea, vomiting, dry mouth and dizziness. Dyskinesias (abnormal movements) may occur as the dose is increased. In some individuals, levodopa may cause confusion, hallucinations, or psychosis. Response fluctuations may occur after 2-3 years of use.
COMT inhibitors:
- entacapone (Comtan®)--available in the United States and many other countries.
- tolcapone* (Tasmar®)--available in the United States, but not Canada or Europe.
*Because of concerns for liver toxicity, tolcapone is only indicated for patients whose symptoms are not adequately controlled by other medications. People taking tolcapone must have blood drawn periodically to monitor the liver function.
Side effects include diarrhea and dyskinesias.
Dopamine agonists:
- bromocriptine (Parlodel®)
- pergolide (Permax®)
- pramipexole (Mirapex®)
- ropinirole (Requip®)
- cabergoline* (Dostinex®)
- apomorphine (Apokyn®)
- lisuride** (Dopergine®)
* Not currently approved in the United States for the treatment of PD
**Not currently available in the United States
Side effects include drowsiness, nausea, vomiting, dry mouth, dizziness, and feeling faint upon standing. While these symptoms are common when starting a dopamine agonist, they typically resolve over several days. In some individuals, dopamine agonists may cause confusion, hallucinations, or psychosis. Sleepiness, drowsiness, or sedation may be a significant side effect of some dopamine agonists in some people, and may interfere with driving or other activities.
Amantadine
Side effects may include difficulty in concentrating, confusion, insomnia, nightmares, agitation, and hallucinations. Amantadine may cause leg swelling as well as mottled skin, often on the legs.
Anticholinergic medications:
- Biperiden HCL (Akineton®)
- Benztropine mesylate (Cogentin®)
- Procyclidine (Kemadrin®)
- Trihexyphenidyl (Artane®)
Side effects may include dry mouth, blurred vision, sedation, delirium, hallucination, constipation, and urinary retention. Confusion and hallucinations may also occur.
Selegiline preparations:
- Eldepryl®
- Atapryl®
- Carbex®
Side effects may include heartburn, nausea, dry mouth, and dizziness. Confusion, nightmares, hallucinations, and headache occur less frequently and should be reported to your physician.
Protective treatments
Current symptomatic treatments (PD medications) can significantly impact on the management of the disease. They do not, however, prevent disease progression. There is great interest in the development of neuroprotective therapies to halt the disease or delay its onset. Cell loss in the substantia nigra is the cause of symptoms of PD. The reason that it occurs is unclear. The occurrence of certain chemical reactions involving oxidation results in the production of substances (such as so-called free radicals or reactive oxygen species) that may be harmful to cells and lead to their deaths. Such oxidative stress may thus be important with regard to the development of PD. Neuroprotective treatments may be most helpful at an early stage of PD, and this stresses the need for finding a simple biological marker. This would enable treatment to be initiated at the preclinical or early clinical phase of the disease.
Selegiline is an inhibitor of the enzyme MAO-B (monoamine oxidase B). Since this enzyme breaks down dopamine, inhibiting it prolongs the action of dopamine in the brain, and may improve the symptoms of Parkinson's disease. It also has a mild antidepressant effect. While early studies of selegiline initially led physicians to believe that it may delay the progression of Parkinson's disease, currently there is no firm evidence that this is so. Nevertheless, there are theoretical grounds to believe it may slow the disease.
Levodopa: there is controversy as to whether this medication is toxic to neuronal cells or protective. There is no evidence that it worsens or slows the progression of Parkinson's disease.
Coenzyme Q-10: Cells need energy to survive and function. They contain mitochondria, which are “batteries” that produce energy. In Parkinson's disease, there seems to be a disturbance in the function of these batteries. Coenzyme Q10 seems to affect this energy-generating mechanisms in cells, although the exact mechanism remains a mystery. A recent study suggested that treatment with 1200 mg/day of coenzyme Q10 resulted in improvements in measures of motor function over the fixed period of the study when compared to lower doses of the same compound or to a placebo compound. Coenzyme Q-10 was also found to be safe in this trial. A larger trial sponsored by NIH and the Parkinson Study Group is underway which will test 1200mg or 2400mg versus a placebo compound.
Dopamine agonists have been shown experimentally to protect dopamine cells. They may have antioxidant effects, inhibiting free radical formation and scavenging free radicals. They may also slow programmed cell death (apoptosis) which may be accelerated in Parkinson's disease.
Experimental Treatments
Many patients inquire about "restorative" therapies, a category of procedures that includes transplantation of fetal cells or stem cells, growth factors, or gene therapy. The goal of these procedures is to correct the basic chemical defect of Parkinson's disease by increasing the production of dopamine in the brain. Although theoretically very attractive, much more laboratory work must be done in order to make cell transplantation or growth factor therapies practical and effective. At this time, the restorative therapies are experimental and are not available as treatment.
WEBSITES
Information Regarding Ongoing Clinical Trials and Research:
The Parkinson Study Group (PSG)
University of Rochester
1351 Mt. Hope Avenue, Suite 220
Rochester, NY 14620
www.parkinson-study-group.org
National Institute of Neurological Disorders and Stroke (NINDS)
BRAIN
P.O. Box 5801
Bethesda, MD 20824
Tel: (800) 352-9424
TTY (for people using adaptive equipment) (301) 468-5981
www.ninds.nih.gov
Experimental Therapeutics Branch (ETB)
Room 4N212 [MSC 1380]
National Institute of Mental Health
10 Center Drive
Bethesda, MD 20892-1380
http://intramural.nimh.nih.gov/research/etb/index1.htm
Surgical Treatments
When should surgical treatment be considered?
For most people with Parkinson's disease, levodopa and other medications are effective for maintaining a good quality of life. As the disorder progresses, however, some patients develop variability in their response to treatment, called “motor fluctuations.” During an “on” period, a person can move with relative ease, often with reduced tremor and stiffness. “Off” periods describe those times when a person is having more difficulty with movement. A common time for a person with Parkinson's disease to experience an “off” period is just prior to taking the next dose of levodopa, and this experience is called “wearing off.” Another form of motor fluctuation is uncontrolled writhing movement (choreiform movement) of the body or a limb, which is called “dyskinesia.” For most people with Parkinson's disease, wearing off and dyskinesias can be managed with changes in medications (see the “Medications for Parkinson's disease" section above). However, when medication adjustments do not improve mobility or when medications cause significant side effects, surgical treatment may be considered.
What are the Different Types of Surgery for Parkinson's disease?
The different types of surgery for Parkinson's disease are summarized in the table below. The first surgical procedures developed were the “ablative or brain lesioning” procedures. Examples of lesioning surgery include thalamotomy and pallidotomy. In lesioning, a surgeon uses a heat probe to destroy a small region of brain tissue that is abnormally active in Parkinson's disease. No instruments or wires are left in the brain after the procedure, which produces a permanent effect on the brain. In general, it is not safe to perform lesioning on both sides of the brain. Thalamic surgery is generally reserved for patients with essential tremor and is not recommended any longer for patients with Parkinson's disease.
Overview of Neurosurgical Procedures for Parkinson’s Disease.
- Procedure
- Effect of Procedure
- Lesioning Procedures
- Thalamotomy (thalamus)
Proven benefit for tremor only
- Pallidotomy (globus pallidus)
Proven benefit for tremor, rigidity, bradykinesia, and levodopa-induced dyskinesias. Not recommended for use on both sides of the brain.
- Deep Brain Stimulation Procedures
- Thalamic (thalamus) stimulation
- (Vim DBS)
Reduces tremor but not the other signs of PD; approved by U.S. Food & Drug Administration (FDA) in 1997
- Pallidal (globus pallidus) stimulation
- (GPi DBS)
Reduces tremor, rigidity, bradykinesia, and gait disorder; approved by FDA in 2002
- Subthalamic nucleus (STN DBS)
Reduces tremor, rigidity, bradykinesia, and gait disorder; approved by FDA in 2002
In addition to lesioning surgery, many surgical teams now offer an alternative treatment called deep brain stimulation (DBS). DBS surgery involves placing a thin metal electrode (about the diameter of a piece of spaghetti) into one of several possible brain targets and attaching it to a computerized pulse generator, which is implanted under the skin in the chest (much like a heart pacemaker). All parts of the stimulator system are internal; there are no wires coming out through the skin. To improve control of symptoms, the stimulator can be adjusted during a routine office visit by a physician or nurse using a programming computer held next to the skin over the pulse generator. Unlike lesioning, DBS does not destroy brain tissue. Instead, it reversibly alters the abnormal function of the brain tissue in the region of the stimulating electrode. Although deep brain stimulation is a major new advance, it is a more complicated therapy that may demand considerable time and patience before its effects are optimized.
What are the possible brain targets for DBS?
There are now three possible target sites in the brain that may be selected for placement of stimulating electrodes: the globus pallidus (GPi), the subthalamic nucleus (STN), and the thalamus (the specific region of thalamus is called “Vim” (ventro-intermediate nucleus). These structures are small clusters of nerve cells that play critical roles in the control of movement. The effects of stimulating these brain regions are indicated in Table 1. Thalamic (Vim) stimulation is only effective for tremor, not for the other symptoms of PD. Stimulation of the globus pallidus or subthalamic nucleus, in contrast, may benefit not only tremor but also other parkinsonian disturbances such as rigidity (muscle stiffness), bradykinesia (slow movement), and gait problems. For most patients with PD, DBS of the globus pallidus or subthalamic nucleus are more appropriate choices than thalamic DBS because stimulation at these targets affects a broader range of symptoms.
How does DBS work?
The theoretical basis for DBS of the GPi or STN in PD was worked out in the late 1980s and early 1990s. In PD, loss of dopamine-producing cells leads to excessive and abnormally patterned activity in both the GPi and the STN. “Pacing” of these nuclei with a constant, steady-frequency electrical pulse corrects this excessive and abnormal activity. DBS does not act directly on dopamine-producing cells and does not affect brain dopamine levels. Instead, it compensates for one of the major secondary effects of dopamine loss, the excessive and abnormally patterned electrical discharge in the GPi or the STN. The mechanism by which the constant-frequency stimulation pulse affects nearby brain cells has not been determined.
How is the surgery performed?
The procedure for performing lesion surgery or implanting a brain electrode varies somewhat from one medical center to another. Typically these operations are performed with the patient awake, using only local anesthetic and occasional sedation. The basic surgical method is called stereotaxis, a method useful for approaching deep brain targets though a small skull opening. For stereotactic surgery, a rigid frame is attached to the patient's head just before surgery, after the skin is anesthetized with local anesthetic. A brain imaging study (usually MRI) is obtained with the frame in place. The images of the brain and frame are used to calculate the position of the desired brain target and guide instruments to that target with minimal injury to the brain.
After frame placement, MRI, and calculation of the target coordinates on a computer, the patient is taken to the operating room. At that point sedative medication is given and a patch of hair on top of the head is shaved. After administration of local anesthetic to the scalp to make it completely numb, an incision is made on top of the head behind the hairline and a small opening (1.5 centimeters, about the size of a nickel) is made in the skull. At this point, all intravenous sedatives are turned off so that the patient becomes fully awake.
To maximize the precision of the surgery, some surgical teams employ a “brain mapping” procedure in which fine microelectrodes are used to record brain cell activity in the region of the intended target to confirm that it is correct, or to make very fine adjustments of 1 or 2 mm in the intended brain target if the initial target is not exactly correct. The brain mapping produces no sensation but patients must be calm, cooperative, and silent during the mapping or else the procedure must be stopped. The brain’s electrical signals are played on an audio monitor so that the surgical team can hear the signals and assess their pattern. Since each person’s brain is different, the time it takes for the mapping varies from about 30 minutes to up to 2 hours for each side of the brain. The neurological status of the patient (such as strength, vision, and improvement of motor function) is monitored frequently during the operation by the surgeon or neurologist.
The procedures for lesion surgery and DBS differ once the target site has been confirmed by microelectrode recording. In the case of lesion surgery, a computer-controlled probe is used to create the desired lesion. This may take several minutes and some of the benefits may be observed immediately. Once the desired lesion has been made, the probe is removed and the skull and scalp are closed surgically.
If a person undergoes DBS implantation, once the target site has been confirmed by microelectrode recording, the permanent DBS electrode is inserted. After the DBS electrode is inserted and tested, intravenous sedation is resumed to make the patient sleepy. The electrode is anchored to the skull with a plastic cap, and the scalp is closed with sutures. The patient then receives a general anesthetic and is completely asleep for the placement of the pulse generator in the chest and positioning of a connecting wire between the brain electrode and the pulse generator unit. This part of the procedure takes about 40 minutes.
Would both sides of the brain be done at once, or only one side?
DBS on one side of the brain mainly affects symptoms on the opposite side of the body. Many patients have symptoms on both sides of the body. DBS leads can be placed on one side or both sides on the same operating day. The decision to place one or two stimulators in one operating day is made according to a patient’s symptoms and general health. For elderly patients, or patients concerned about a longer operation, it may be best to stage the procedures a few weeks or months apart.
What are the benefits of surgery?
The major benefit of surgery for PD is that it makes movement in the off-medication state more like movement in the on-medication state. In addition, it may reduce levodopa-induced dyskinesias. The procedure is most beneficial for PD patients who cycle between states of immobility (“off” state) and states of better mobility (“on” state). Surgical treatments “smooth out” these fluctuations so that there is better function during the day. Symptoms that improve with levodopa (slowness, stiffness, tremor, gait disorder) may also improve with DBS. Symptoms that do not respond at all to levodopa usually do not improve significantly with DBS. Following DBS, there may be a reduction in need for, but not elimination, of antiparkinsonian medications. At present, it is believed that DBS only suppresses symptoms and does not alter the underlying progression of PD.
What are the risks of pallidotomy or DBS surgery?
The most serious potential risk of the surgical procedures is bleeding in the brain, producing a stroke. This risk varies from patient to patient, depending on the overall medical condition and on the surgeon, but the average risk is about 2%. If stroke occurs, it usually does so during or within a few hours of surgery. The effects of stroke can range from mild weakness that recovers in a few weeks or months to severe, permanent weakness, intellectual impairment, or death.
For DBS some additional risks apply. The second most serious risk is infection, which occurs in about 4% of patients. If an infection occurs, it is usually not life-threatening, but it may require removal of the entire DBS system. In most cases, a new DBS system can be re-implanted when the infection is eradicated. Finally, hardware may break or erode through the skin with normal usage, requiring it to be replaced. In the first few days after surgery, it is normal to have some temporary swelling of the brain tissue around the electrode. This may produce no symptoms, but it can produce mild disorientation, sleepiness, or personality change that lasts for up to 1-2 weeks.
What makes a patient a good candidate surgical treatment for Parkinson's disease?
Deciding whether a person is a good candidate for surgical treatment is best determined by an evaluation by a neurologist or neurosurgeon familiar with the surgical treatment of Parkinson's disease. In reviewing the outcome of many people who have undergone surgical treatment for Parkinson's disease, the patients who derive the most benefit have good general health, normal intellectual and memory function for their age, and continue to experience benefit (however short) from levodopa.
Can patients control the DBS device themselves?
Following surgery, the patient is given the Medtronic Access Review unit, a hand-held battery-operated unit that can be used to determine whether the device is on or off, to turn it on or off, and to check battery life. The device does not at this time allow the patient to alter the intensity of stimulation. This is done in the physician’s office. Normally, in DBS for Parkinson's disease, the device is left on all the time. The next generation of DBS devices may allow some patient control over the intensity of stimulation
Is DBS surgery covered by health insurance?
Medicare now covers DBS for Parkinson's disease. Insurance approval should be sought prior to hospital admission. There may be variation on private insurance coverage.
The above information was contributed by Mariann Di Minno, RN, MA, and Michael J. Aminoff, MD, DSc, of the Parkinson’s Disease Clinic and Research Center at the University of California, San Francisco.