Care of the PD patient requires a multidisciplinary team approach, including important aspects such as patient education, exercise, diet, and rehabilitation services. Patients and their families should be educated about the natural history of PD and available treatments and resources. Support groups are particularly valuable. As the disease progresses and new symptoms and complications arise, treatment regimens can become complex. Patients will need to learn to differentiate among symptoms related to PD, medication side effects, or other conditions. Exercise improves mood, strength, balance, flexibility, and mobility. A combination of aerobic, strengthening, and flexibility exercises can maintain functional status. A well-balanced healthy diet and adequate hydration can prevent constipation and orthostatic hypotension. Furthermore, protein restriction may be necessary in some patients, as amino acids compete with levodopa for absorption, thus blocking its therapeutic effect. Involving a nutritionist may be vital, especially as weight loss and disuse atrophy can occur and are associated with poor outcomes. Physical, occupational, speech, and swallowing rehabilitation therapies aimed at improving daily function and QOL can be effective at all stages. Emotional and psychological needs of the patient and family should also be addressed through counseling of a chaplain, psychiatrist, psychologist, or other mental health provider.
PD is an incurable illness, with no treatments proven to slow disease progression. However, PD is somewhat unique among neurodegenerative disorders in that it benefits from a diverse range of effective symptomatic treatments such as dopaminergic medications. The primary goal of pharmacotherapy is to reduce symptoms to maintain independence, functional status, and QOL and reduce disability. A common misconception among patients (and clinicians) is that medications will “only last for so long” once started. This now discredited belief has led to an all-too-common practice of delaying treatment as long as possible. Treatment should be initiated and tailored to adequately reduce symptoms whenever patients are bothered by their symptoms, and certainly when functional status, independence or mobility is threatened. Many PD patients, especially young-onset and tremor/motor-predominant patients, can lead highly functional lives for many years with optimized treatment regimens. However, as the disease progresses, complications of dopaminergic medications, such as dyskinesia and motor fluctuations, occur and regimens can become complex. Especially in older adults, medications can exacerbate nonmotor symptoms, such as visual hallucinations, behavioral problems, orthostasis, and somnolence, and reductions may be necessary at the cost of decreased motor benefit.
Levodopa is the most effective and well-established drug in the treatment of PD. Converted by DOPA-decarboxylase into dopamine, it provides dopaminergic replacement. It ameliorates tremor, bradykinesia and rigidity, thus reducing morbidity and disability. Axial features of PD such as speech and gait impairment are frequently less responsive to levodopa and other dopaminergic medications. Furthermore, in advanced PD, postural instability, speech impairment, autonomic dysfunction, dementia and psychiatric problems are not responsive to levodopa. Although levodopa does not slow the progression of PD pathology, life expectancy in PD has drastically improved today compared to the prelevodopa era.
Levodopa provides a robust and consistent improvement of motor features, and keeps patients highly functional for years. However, the vast majority of advanced patients will eventually experience motor complications, namely motor fluctuations and dyskinesia, manifest as inconsistent response to levodopa. In the earlier stages, patients experience “wearing off,” where the duration of effect of each levodopa dose progressively shortens, and requires shorter intervals between doses. Later on, more unpredictability occurs, with some doses completely failing to “kick in,” and others abruptly losing effect. Dyskinesias are involuntary hyperkinetic movements that occur at “peak-dose” levodopa levels. They are most commonly choreiform (abnormal twisting, writhing, dance-like movements) but can also be dystonic (pulling into more sustained and often painful postures).
Other side effects of levodopa include nausea, vomiting, lightheadedness, dizziness, somnolence, and, in more advanced patients, hallucinations and confusion. Peripheral decarboxylase inhibitors, such as carbidopa are always included in formulations of levodopa to reduce the gastrointestinal side effects by preventing peripheral conversion of levodopa to dopamine. Isolated carbidopa can be added to prevent the nausea experienced with standard levodopa formulations. Levodopa is generally a well-tolerated medication and most side effects can be avoided if started slowly and gradually titrated up to an effective dose. It should be taken on empty stomach at least 30–45 minutes before or after meals, to avoid protein blocking of absorption of levodopa. Long-acting formulations of levodopa (eg, Sinemet CR) are helpful for bedtime dosing as they can reduce nocturnal return of PD symptoms, but daytime use of these formulations can exacerbate complications.
Dopamine agonists directly stimulate dopamine receptors in the striatum (the postsynaptic target of nigral neurons). The older ergot derivatives such as bromocriptine and pergolide are not used in clinical practice because of serious side effects such as heart valve damage. Newer nonergot agonists, such as pramipexole, ropinirole, and transdermal rotigotine, have replaced them. Dopamine agonists are effective as monotherapy in reducing cardinal motor features of PD. However, within 2–5 years, most patients will require the addition of levodopa. Dopamine agonists are also used as adjunctive therapy with levodopa when motor complications occur. As they are longer-acting, they can reduce the severity of “wearing off,” and as they cause less dyskinesia than levodopa, they are sometimes used in order to attempt a decreased levodopa dose.
Dopamine agonists are poorly tolerated in older adults. Although side effects are similar to levodopa (nausea, vomiting, orthostatic hypotension, somnolence, dizziness, psychiatric symptoms, hallucinations), they occur more commonly and more severely, especially in older adults. Serious consideration should be given before starting a dopamine agonist in patients older than 70 years of age because of the side effects of somnolence, cognitive impairment, and psychosis. Dopamine agonists also have additional side effects, including impulse control disorder, that are rarely seen with levodopa. Patients on dopamine agonists should be educated about and frequently screened for compulsive gambling, eating, and shopping, hypersexuality, and other impulsive behaviors.
Levodopa and dopamine agonists are the 2 main drug classes used as monotherapy in PD. Other PD drugs have minimal symptomatic benefits when used alone and serve as adjunctive therapy when motor complications occur. As most patients require these medications when they have entered the more complicated moderate to advanced stage of PD, one should consider consulting a neurologist before initiating these agents. COMT inhibitors (entacapone and tolcapone) and MAO-B inhibitors (selegiline and rasagiline) block the enzymatic breakdown of levodopa and are used to decrease motor fluctuations (“wearing off”) by extending the duration of benefit of each dose of levodopa. Amantadine is the only medication with proven effectiveness for reducing dyskinesia. It reduces tremor and freezing of gait in some patients as well. Amantadine has dopamine agonist and anticholinergic properties, commonly exacerbates somnolence, cognitive impairment and psychosis, and has limited use in older adults. Similarly, anticholinergic medications like trihexyphenidyl can be effective at reducing tremor, dyskinesia, and dystonia, but older patients have low tolerance for their cognitive and autonomic impairment. These drugs should not be considered options in the geriatric population.
In many patients, medications become progressively less effective in relieving PD symptoms consistently, especially after the onset motor fluctuations or dyskinesia. Some of these patients may benefit from surgical therapies. Candidacy for these interventions is complex. The ideal candidate is a patient who has a clear diagnosis of PD, continued good response to medications in the “on” state, suffers from disabling motor complications despite optimal medical management, is healthy enough to tolerate a neurosurgical intervention, has relatively intact cognition and does not suffer from a significant or uncontrolled mood disorder. There is no firm age-limit, but patients older than age 70 years are generally considered higher risk, and those older than age 80 years are rarely operated on.
Pallidotomy (lesioning of the GPi) is effective in treating the cardinal features of PD and can drastically reduce levodopa-induced dyskinesias. Similarly, thalamotomy can reduce tremor. However, these lesioning procedures are irreversible, not adjustable, and bilateral procedures that are associated with dysphagia, dysarthria, and cognitive impairment. Consequently, today these procedures are mostly used only in situations where DBS is not feasible.
DBS of subthalamic nucleus (STN) or GPi has mostly replaced stereotactic lesioning procedures. Although more expensive, DBS has the advantages of being nondestructive, reversible, and programmable. Bilateral procedures are better tolerated. The DBS system is a 4-contact lead implanted into each hemisphere of the brain by stereotactic technique. The leads are connected to a pulse generator in the chest wall by subcutaneous extension wires. Clinicians program the device for optimal benefit to avoid side effects by adjusting the amplitude, pulse width, frequency and polarity of stimulation, and by changing the configuration of active contacts on each lead. Patients can also make some adjustments at home.
DBS of both targets can alleviate the cardinal features of PD, motor fluctuations, and dyskinesia. Both targets are effective at treating tremor, rigidity, and bradykinesia, especially in the limbs. However, as with medications, axial symptoms such as gait and speech are less responsive to DBS. In fact, DBS can make speech, falls, cognition, and behavioral symptoms worse, especially in high-risk patients. It is important to have extensive discussion with patients and their families before surgery to make sure that the symptoms that bother them the most (ie, their goals of treatment) match those that can be reliably alleviated by DBS. The largest recent randomized clinical trial found these 2 targets to have similar effectiveness and safety. However, STN-DBS has higher risk of falls and cognitive and mood side effects.
DBS has higher risk of infection and hardware problems than ablative procedures. Some side effects, such as speech impairment, spasticity, and mood changes, can result from stimulation of neighboring structures in the brain. Adjusting stimulation parameters often alleviates these stimulation-induced side effects.