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Medical Management of Parkinson's Disease
by Ken Nakamura, MD, PhD
Department of Neurology, University of California, San Francisco
Lecture related to:
Chapter 351: Parkinson's Disease and Other Movement Disorders
Slide 1: Medical Management of Parkinson's Disease
Ken Nakamura, MD, PhD, Department of Neurology, University of California, San Francisco.
Slide 2: Parkinson's Disease
The cardinal features of Parkinson's disease are resting tremor, rigidity, bradykinesia, and postural instability. These motor symptoms primarily result from the degeneration of dopaminergic neurons in the nigrostriatal system. However, the severity of motor deficits varies widely among patients. Many patients also develop other problems such as depression, cognitive dysfunction, sleep disturbances, and autonomic dysfunction. (Merritt's Textbook of Neurology, 9th Edition, 1994, Williams & Wilkins)
Slide 3: Medical Management of Parkinson's Disease
As a result, medical therapy must be tailored to the specific needs of each patient, at each stage of the disease.
Slide 4: Goals of Treating the Mildly Symptomatic Patient
At the time of diagnosis, the symptoms of Parkinson's disease are often mild and not yet significantly affecting quality of life. At this stage, the primary goals of medical therapy are to delay disease progression, without impairing the benefit of future therapies. Unfortunately, no medication has been definitively shown to modify the disease course. There is weak evidence suggesting that several medications including selegiline, rasagiline, and coenzyme Q10 may have neuroprotective properties, and hence some physicians choose to prescribe these medications at this stage.
Slide 5: Selegiline
Most physicians are aware of the Datatop study, which revealed that the effects of selegiline are mainly symptomatic. There is also some evidence that selegiline, an MAO-B inhibitor, may prevent the development of freezing of gait, a motor complication that can develop in advanced Parkinson's disease. However, the interpretation of these data remains controversial among movement disorder specialists, with a minority of physicians choosing to treat mildly affected patients with selegiline. Selegiline can be administered at 5 mg BID. At this dose, it is generally well tolerated. The most common adverse effect is insomnia, due to the formation of amphetamine metabolites.
Slide 6: Rasagiline
Rasagiline is a new MAO-B inhibitor that is not metabolized to amphetamine-like products. Rasagiline has been found to have symptomatic benefits when used both as monotherapy in early PD, and as an adjunctive therapy in more advanced stages. Preliminary evidence from clinical trials and animal models of Parkinson's disease suggests that rasagaline may also have neuroprotective effects. This is being further evaluated in ongoing clinical trials.
Slide 7: Neuroprotective Effects of Coenzyme Q10??
In recent years, coenzyme Q10 has received considerable attention for its potential neuroprotective effects. Currently, the evidence for this stems from theory and the results of a single pilot study of 80 patients followed for 16 months (Shults et al., Arch Neurol 2002; 59:1541-1550). In this study, patients were randomly assigned to receive either placebo or coenzyme Q10 at doses of 300, 600, or 1200 mg/d. Patients treated with the highest dose showed slightly less worsening in UPDRS scores than placebo. This finding was of borderline significance (p = .04). The drug was well tolerated, with no significant adverse effects. The significance of these results is unclear and awaits confirmation by a larger randomized clinical trial.
Slide 8: Nonpharmacologic Treatments
Non-pharmacologic approaches could represent the most effective available therapies for patients at the early symptomatic stage. For instance, many physicians have the impression that regular exercise emphasizing flexibility, balance, and mobility improves long-term outcome. Frequent cognitive stimulation is also widely felt to be beneficial. However, the mechanism by which these approaches might be useful are unclear, and neither has been rigorously tested by clinical trials.
Unfortunately, there are also no dietary or environmental interventions that have been clearly shown to lower the incidence or slow the progression of Parkinson's disease. A large number of environmental exposures have been weakly associated with the disease, but causality has never been established.
Slide 9: Intermediate PD—Early Treatment
When quality of life begins to become impaired, symptomatic treatment is indicated. However, it is important that these therapies do not accelerate disease progression, or compromise the effectiveness of future therapies.
An ongoing debate centers on when therapy with levodopa should be initiated, or whether one should begin treatment with a dopamine agonist. Depending on the situation, either may be reasonable. Despite being the most effective symptomatic pharmacologic therapy for Parkinson's disease, there are long-standing concerns as to whether levodopa might accelerate disease progression, possibly by promoting dopamine toxicity.
Slide 10: Levodopa Toxicity??
Unfortunately, despite multiple studies, it remains unclear whether levodopa therapy has an effect on the rate of neurodegeneration in Parkinson's disease. In one prominent trial, the ELLDOPA study (The Parkinson Study Group, NEJM 351(24):2498-2508, 2004), patients were treated with increasing doses of levodopa for 40 weeks, followed by a 2-week wash out period. Following this washout, patients treated with levodopa had better UPDRS scores than controls. Although these data could suggest a neuroprotective effect, it remains unclear whether the washout period was long enough to fully negate the symptomatic effects of levodopa.
Slide 11: Levodopa Toxicity??
Adding to the confusion, in the same study, the striatal uptake of a substrate for the dopamine transporter (ß-CIT) decreased to a greater extent in patients treated with levodopa than placebo. This apparently contradictory result could indicate the death of dopaminergic neurons, which express the dopamine transporter. However, an alternative possibility is that the decrease in ß-CIT binding actually reflects secondary changes in the expression or activity of the dopamine transporter. (The Parkinson Study Group, NEJM 351(24), 2004)
Slide 12: Levodopa and Dyskinesias
What does seem clear is that delaying the initiation of levodopa therapy can delay the onset of potentially disabling abnormal involuntary movements known as dyskinesias. This table summarizes the findings from two large studies of patients with early Parkinson's disease, comparing the risk of developing dyskinesias following treatment with dopamine agonists versus levodopa alone. In both cases, the proportion of patients who developed dyskinesias was more than 50% less in the agonist group. Note that supplementary levodopa was allowed in the agonist group in both studies, likely decreasing the magnitude of the finding.
So why not start every new patient on a dopamine agonist? First, as you can see, in these studies agonists were less effective than levodopa in providing symptomatic control. Clearly, levodopa is still the most effective symptomatic drug therapy for Parkinson's disease. Second, as we will discuss, agonists often produce more adverse effects than levodopa. For these reasons, older patients-who are typically more prone to medication-induced adverse effects-are often started on levodopa at the time of diagnosis.
It is worth mentioning that some clinicians feel that the development of dyskinesias can also be avoided by maintaining smoother plasma levels of levodopa from the time that therapy is initiated. However, besides being difficult to achieve, the long term validity of this concept has not yet been established in humans.
Another controversial point centers around the concept of priming. In animal studies, early exposure to levodopa can predispose individuals to develop dyskinesias in the future when they are re-exposed to levodopa. Once again, it is unclear whether this applies to humans, but some clinicians prefer to avoid giving any levodopa at all in the early stages of Parkinson's disease, when other medications often provide adequate symptom control.
Slide 13: Dopamine Agonists
Although there are several dopamine agonists available, the majority of patients are treated with either pramipexole or ropinirole. These medications are non-ergot derivatives, have longer half lives than levodopa, and are typically administered three times per day. Patients are generally started on low doses and gradually titrated upwards until symptoms are controlled, or adverse effects develop. Patients should be warned about potential side effects, which can include somnolence, sudden sleep attacks, hallucinations, behavioral changes, and lower extremity edema. Dopamine agonists derived from ergots are less commonly used, as they have been associated with retroperitoneal fibrosis and other fibrotic complications. An added association between one ergot agonist, pergolide, and cardiac valvular abnormalities has recently been described. Patients treated with pergolide should be followed by serial cardiac echocardiography.
Slide 14: Carbidopa/Levodopa
In patients who are elderly and/or susceptible to the adverse effects of dopamine agonists, it is reasonable to use levodopa as the initial therapy. Levodopa is administered in combination with carbidopa. Carbidopa prevents the peripheral conversion of levodopa into dopamine. This increases the amount of levodopa that crosses the blood brain barrier, while also decreasing adverse effects that result from the peripheral production of dopamine. Benseraside, available in Europe, fulfills a similar role as carbidopa.
Although levodopa remains the most effective pharmacologic therapy for motor dysfunction in Parkinson's disease, not all symptoms are equally responsive. In particular, tremor may be difficult to treat. Levodopa is also typically less effective for the axial, cognitive, psychiatric, autonomic, and sensory symptoms of Parkinson's disease. This is probably because Parkinson's disease also involves the degeneration of many neuronal types outside of the nigrostriatal system.
Slide 15: Adverse Effects of Carbidopa/Levodopa
Although generally well tolerated, levodopa does have a number of common side effects. Foremost among these is nausea. Nausea can result from the peripheral conversion of levodopa to dopamine. Therefore, it is important to ensure that patients who develop nausea are taking enough carbidopa. Typically 75-100 mg/d is sufficient. However, some patients may require up to 300 mg per day, which can be administered as supplemental carbidopa. Note that levodopa is typically administered away from meals, so as to ensure consistent and maximal absorption, which can be impaired by protein-containing foods. However, avoiding mealtime dosing of levodopa may not be necessary early in the disease, when symptoms are mild. Patients with mild Parkinson's disease who experience nausea may find that gastrointestinal symptoms are reduced when levodopa is taken with meals. For those patients with refractory nausea, select antiemetics can be considered. However, care must be taken to avoid antiemetics such as metoclopramide and prochlorperazine, which may exacerbate parkinsonism. Potential options include serotonin 5HT-3 receptor antagonists, such as ondansetron, and domperidone (the latter is not available in the United States).
Postural hypotension is another common side effect of levodopa. Patients must be warned of this possibility and take precautions when doses are increased. In some cases, patients on anti-hypertensive regimens may need them modified. Hallucinations, compulsive behaviors, somnolence and other neuropsychiatric changes can also result from levodopa, although they tend to be less common than with dopamine agonists. Yet another common adverse effect of levodopa is abnormal involuntary movement, known as dyskinesia. This will be discussed in more detail later.
Slide 16: Levodopa Dosing and Formulations
Levodopa is available in immediate release (IR) and controlled release (CR) preparations. The immediate release form is often initiated at 25/100 BID or TID and gradually titrated upwards, as required for symptom control and as tolerated. In some cases, patients require at least 1000 mg/d before they notice significant benefit.
Early in the disease, the controlled release formulation of levodopa may be effective. However, because the bioavailability of this form is lower (roughly 75% of the immediate release formulation), and because the time course of absorption is erratic, the immediate release form is usually more predictable in its effects as the disease becomes more advanced.
One tablet of controlled release carbidopa/levodopa 50/200 is often useful at bedtime, where the extended duration of action may help control symptoms throughout the night.
However, patients must be closely monitored since in some cases, bedtime dosing of dopaminergic medications actually interferes with sleep.
Slide 17: Advanced Disease
After initiating pharmacologic therapy, patients often experience several to many years of good symptomatic control. However, as the underlying disease progresses, and dopaminergic neurons continue to degenerate, the ability of the brain to take up and store dopamine decreases. As this occurs, the therapeutic window narrows, and patients require higher and more frequent doses of levodopa, while also becoming more susceptible to medication-induced adverse effects.
During this advanced phase of the disease, therapy is primarily directed at treating symptoms and minimizing and/or treating medication-related adverse effects. Of course, the ability to delay any further disease progression would still be ideal.
Slide 18: Motor Fluctuations
With advanced disease, patients can develop several types of motor fluctuations. First, medication effects may begin to wear off before the next dose. When this occurs, the dosing interval can be shortened. Alternatively, a COMT inhibitor, such as entacapone, can be added to prolong the therapeutic effects of levodopa by reducing the peripheral degradation of levodopa.
"Off" periods are particularly common upon awakening, resulting in early morning stiffness and/or immobility. Patients may benefit from either chewing their first tablet of carbidopa/levodopa, crushing and dissolving the tablet in water, or using a sublingual dissolvable form, so as to promote faster absorption and therapeutic effect.
A particularly disabling motor fluctuation is sudden, unpredictable wearing off, where patients may experience significant and persistent immobility. For such episodes, treatment with subcutaneous apomorphine, a rapid but short-acting dopamine agonist, may be beneficial to rescue patients from these extreme states. Note that before beginning this medication, patients typically require pre-treatment with an antiemetic to avoid nausea.
Slide 19: Dyskinesias
Patients with advanced Parkinson's disease also frequently develop dyskinesias. Dyskinesias are abnormal involuntary movements, most commonly occurring at peak-dose (usually 30-60 min after levodopa dosing), when plasma dopamine levels are maximal. These dyskinesias are most commonly choreiform in nature. A less common form of dykinesia is known as diphasic dyskinesia. These dyskinesias occur both during the rise and fall of plasma levodopa levels, often involve the legs, and may be choreiform or dystonic in nature.
Dyskinesias are generally treated in conjunction with a movement specialist. Typically, patients with peak-dose dyskinesias are treated with more frequent, smaller doses of levodopa, in an attempt to maintain lower and smoother levels of levodopa. In general, the immediate release form of levodopa should be used (rather than controlled release), so as to maximize the reliability of dosing. Patients with refractory dyskinesias can also be treated with amantadine, which can be started at 100 mg once per day, and titrated to 100 mg TID. Adverse effects of this medication include gastrointestinal upset, leg swelling, livedo reticularis, and cognitive changes.
Slide 20: Nonmotor Symptoms—Sleep Disorders
Sleep disorders are common in Parkinson's disease. First, rigidity and immobility may result in difficulty falling or staying asleep. In some cases, this may be helped by the addition of controlled release levodopa immediately before sleep. In more severe cases, patients may need additional doses of levodopa during the night. Many patients with Parkinson's disease also develop restless legs syndrome, in which they experience an uncomfortable urge to move their legs, especially when trying to fall asleep. This can be treated with a variety of medications, including dopamine agonists. Another common sleep disorder in Parkinson's disease is REM sleep behavior disorder. Patients may inadvertently strike or kick their partners while sleeping, sometimes causing injuries. Fortunately, this can usually be controlled with low dose clonazepam. Yet another frequent cause of poor sleep in Parkinson's patients is nocturia, and patients may benefit from treatment with low dose anticholinergics like oxybutynin.
On the other end of the spectrum, dopamine agonists can cause excessive somnolence, sometimes with sudden sleep attacks. Patients must be warned of this potentially dangerous side effect. Levodopa can also cause excessive somnolence, although this is less common than with dopamine agonists.
Slide 21: Neuropsychiatric Changes in Parkinson's Disease
Patients with Parkinson's disease often develop cognitive changes. Many patients exhibit deficits in attention, planning, and motivation, and a subset develop frank dementia. For these patients, behavioral and environmental modifications represent the primary therapy. Patients with dementia may also benefit from treatment with cholinesterase inhibitors. Despite a theoretical risk, most patients tolerate cholinesterase inhibitors without a worsening of their parkinsonism.
Patients with parkinsonism also frequently experience psychiatric disorders. First, depression is very common, possibly reflecting a direct effect of neural degeneration, in addition to being a secondary response to disability. Patients with depression can be treated with a variety of antidepressants. Selective serotonin reuptake inhibitors are often used as frontline treatment, and are usually well tolerated. Patients with Parkinson's disease also frequently develop visual hallucinations, which are commonly caused by dopaminergic medications and can also be an intrinsic manifestation of the disease. When visual hallucinations develop early in the course of parkinsonism, independent of medications, patients may be diagnosed as having a related disorder known as Lewy Body Dementia. Visual hallucinations are also a common side effect of dopaminergic medications, especially dopamine agonists. When hallucinations cannot be controlled by adjusting the dosing of dopaminergic agents, they may be treated with certain antipsychotic medications. Although many antipsychotic drugs can worsen parkinsonism, low dose quetiapine is often effective, and rarely worsens motor symptoms. Clozapine has a particularly low incidence of exacerbating parkinsonism but requires frequent blood monitoring, due to the risk of agranulocytosis.
Slide 2: Other Non-Motor Issues
Hypophonia is common in Parkinson's disease. Patients should be referred to a speech therapist for evaluation and treatment (a specific technique, Lee Silverman Voice Training, may be particularly beneficial). Patients may also experience a variety of visual problems. These include dry eyes and blepharospasm, which may benefit from saline eye drops and treatment with botulinum toxin, respectively.
Autonomic dysfunction can also be a prominent feature of advanced Parkinson's disease. Constipation is common and can initially be treated with dietary modifications. More severe cases often require standard laxatives. Sialorrhea is also very common in Parkinson's disease, and can be embarrassing to patients. When mild, it usually responds to peripheral acting anticholinergic agents, such as glycopyrrolate. When more severe, botulinum toxin injections into the parotid gland may be helpful. Postural hypotension is particularly common in multiple system atrophy, a related Parkinson-plus syndrome, but also occurs commonly in idiopathic Parkinson's disease. It is important to warn patients that dopaminergic medications can worsen postural hypotension. When severe, postural hypotension can be treated with fludrocortisone and/or midodrine. Sexual dysfunction is yet another common feature of Parkinson's disease. Patient's should be evaluated by urologists and may respond to medications like sildenafil.
Slide 23: DBS
Deep brain stimulation (DBS), a therapy that uses an implantable device to deliver electrical stimulation to motor-controlling regions of the brain, is established as an effective therapy for many patients with advanced Parkinson's disease. DBS is often considered for patients with troubling motor symptoms, despite optimized doses of pharmacotherapy; ideal candidates are still responsive to levodopa, if only briefly, but fail to realize consistent and sustained control of motor symptoms. The subthalamic nucleus (STN) remains the most common target for stimulation, although stimulation of the globus pallidus internus (GPi) is also effective.
Slide 24: Future Therapies
A large array of new therapies for Parkinson's disease are currently under development. Many of these are likely to primarily provide symptomatic benefit, including adenosine antagonists and transdermal patches delivering dopamine agonists. Several approaches designed to modify cells to produce dopamine are also in the early stages of development. These include the transplantation of genetically modified cells, gene transfer using viral vectors, and the use of stem cells. Of note, fetal mesencephalic tissue transplantation has not been found effective in trials to date. A number of trials testing potential disease-modifying therapies, such as coenzyme Q10, and creatine, and neuroprotective approaches, such as trophic factors, are also under development. Of particular importance, there is extensive effort directed towards understanding the pathogenesis of Parkinson's disease, to allow the development of more mechanistically based therapies.
Slide 25: Summary
In summary, the treatment of Parkinson's disease must be tailored to the specific motor and nonmotor signs and symptoms of each patient. Therapy must treat existing symptoms, while being mindful of long-term therapeutic efficacy.
Slide 26: Acknowledgments
I'd like to thank Michael Aminoff and William Marks for their help preparing this presentation.
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