Parkinson disease is a common neurologic disease. It is a progressive, degenerative disease manifested by motor and nonmotor symptoms. First described as a specific syndrome by James Parkinson in 1817 in “An Essay on the Shaking Palsy,” the disease is estimated to affect 1 million people in the United States and 4 million people worldwide. The prevalence in industrialized countries is estimated to be 0.3%. It is rarely seen in patients under 40 years of age, but the incidence increases with age. It is estimated that perhaps 3% of the population over 80 years of age are affected. Multiple studies demonstrate that the onset of Parkinson disease occurs 2 years earlier, on average, in men than in women and that twice as many men as women will develop the disease. Epidemiologic studies have demonstrated few associations. Living in rural areas and exposure to pesticides (specifically paraquat) are risk factors. Smoking and coffee drinking appear to be protective.
CLINICAL PRESENTATION
Parkinson disease is manifested by motor and nonmotor symptoms. The classic findings of Parkinson disease are motor symptoms. These were described in a paper by Hoehn and Yahr in 1967 looking at 183 Parkinson patients. These symptoms include resting tremor, bradykinesia, postural instability, and rigidity. Parkinson disease frequently presents with tremor, usually unilateral. The tremor is typically seen in one extremity initially (sometimes involving only one finger or the thumb). The tremor is slower (4–6 Hz) than a classic essential tremor (8–10 Hz) and is most prominent when the limb is in a posture of repose (the term “resting tremor” is somewhat misleading, as complete relaxation frequently abolishes the tremor). The tremor is suppressed with movement. Less commonly, the head, jaw, and tongue may be involved. For some patients, the classic parkinsonian tremor is the only manifestation of the disease. This is referred to as tremor-predominant Parkinson disease. In our experience, these patients do eventually develop other symptoms of Parkinson disease, but after a period of time, sometimes a number of years.
Bradykinesia refers to slowing of movement and the simplification of complex motor tasks. Spontaneous movement is decreased. This is manifested in the “masked facies” (also known as hypomimia) of Parkinson disease. The blink rate decreases, and the eyes are more open, giving the appearance of staring. The facial muscles move less, so the face is less emotive. As the condition progresses, the mouth often stays slightly open. Speech becomes softer and monotone, with the words running together. Spontaneous swallowing is reduced, and the mechanics of swallowing are affected, resulting in sialorrhea. In Parkinson disease, sialorrhea is due not to increased saliva production but to an inability to efficiently handle saliva. Hand movements become more restricted. Finger tapping may have normal speed, but the amplitude of movement is decreased. Alternating movement becomes difficult, and there is frequent “freezing,” that is, intermittent arrest of motor function. It becomes more difficult to do things such as stir with a spoon or brush one’s teeth. Writing becomes cramped and small (micrographia). Eventually, the patient has difficulty rising from a chair. Changes in gait are noted, with a decrease in arm swing, usually asymmetrically. The length of the patient’s stride diminishes, and arm swing may disappear altogether. The patient can no longer turn on a pivot but turns “en bloc,” using multiple small steps to turn. Eventually, the patient may develop propulsion or retropulsion. The patient’s trunk will “get ahead” of their feet, and they will need to take small running steps to regain their balance, which has been termed festination. As the disease progresses, this may result in the patient falling. Falling, however, generally occurs later in the disease. If a patient tends to fall early in the course of the disease, one should consider a diagnosis other than Parkinson disease.
Nonmotor symptoms of Parkinson disease have become better appreciated over time and can be as debilitating as the motor symptoms. Cognitive decline, depression, anxiety, dysautonomia, and sleep disturbances are all seen with Parkinson disease. Anosmia (loss of the sense of smell) occurs in as many as 90% of patients with Parkinson disease and may precede other symptoms by many years. Dysautonomia is present in virtually all Parkinson disease patients and includes constipation (also a very early symptom). Other gastrointestinal complaints include bloating, nausea, and abdominal discomfort. A study by Hardoff et al. showed slowed gastric emptying times, which were exacerbated by carbidopa levodopa. Orthostatic hypotension is a symptom that presents in some 50% of Parkinson patients; it results in increased debilitation and significantly affects the higher frequency of falling that is seen later in Parkinson disease. Urinary complaints, including increased frequency and urgency, are common. A study of early, untreated Parkinson patients showed abnormal urinary function in the storage phase of 84% of the patients studied. Depression and anxiety are comorbidities with Parkinson disease, present in approximately 35% of patients. Factors such as female sex, dependency, higher United Parkinson disease rating scale scores, and lower Mini Mental status scores may predispose patients to depression. Some data show different forms of depression related to sex. Women feel more melancholy, and men have more apathy and decreased libido. Anxiety occurs with depression or independently of depression. Apathy is seen with or without depression but is more common in patients with cognitive decline.
Dementia in Parkinson disease has a prevalence of 30%–40%. Cereda et al. looked at the onset of Parkinson disease and found that age, sex, and disease duration were independently associated with Parkinson disease, with higher rates of dementia found in men between 60 and 80 years of age. Hallucinations and paranoid ideation are also seen in Parkinson disease, generally in the setting of taking dopaminergic medications. When hallucinations and delusional thinking appear early or in the absence of medication, a diagnosis of Lewy body disease should be entertained.
DIAGNOSIS
A myriad of symptoms are associated with the diagnosis of Parkinson disease. However, many combinations of symptoms exist, and the absence of some symptoms does not necessarily exclude the diagnosis. Actually making the diagnosis, especially early in the disease, relies on the presence of certain cardinal symptoms. The diagnosis may be supported by the presence of certain symptoms or clinical criteria, while the presence of other specific clinical findings would argue against a diagnosis. Experience with the disease on the part of the clinician is helpful, and studies have suggested that experienced clinicians are more accurate in diagnosing Parkinson disease than occurs with the application of a set of diagnostic criteria.
The diagnosis is most strongly supported by the presence of the cardinal manifestations of Parkinson disease, including bradykinesia, rigidity (involuntary resistance to passive movements that are independent of velocity), and rest tremor. The symptoms are not necessarily unilateral but, in classic Parkinson disease, are clearly asymmetric. Not all the symptoms may be present, especially early on, in every patient with Parkinson disease, but the presence of all three clearly strengthens the case for the diagnosis.
The most powerful piece of evidence supporting the diagnosis of Parkinson disease is a clear-cut beneficial response to dopaminergic therapy. The response would be unequivocal with a very obvious improvement in symptoms or significant worsening of symptoms if the drug is withdrawn. If, by history, there is some doubt as to whether there is an improvement of symptoms, one can do an off/on evaluation. This is a test in which the patient comes in having not taken their medication at least for 12 hours. A clinical scale of motor function, most commonly the UPDRS III test, is administered. The patient is then administered their usual dose of dopaminergic medication (or perhaps a slightly higher dose), and a sufficient period of time is allowed for the medication to take effect. The UPDRS III test is then given again. For research purposes, a 30% improvement in score is considered a positive indication that the dopaminergic medication has an impact on the disease. An improvement that is at least close to that should be used as demonstration of clinical benefit in treating the individual patient. In fact, the absence of any significant effect of dopaminergic stimulation in a patient with at least moderate disease symptoms makes the diagnosis of Parkinson disease highly unlikely. However, unlike rigidity and bradykinesia, rest tremor is frequently not responsive to dopaminergic medication in any dose, so a lack of improvement and rest tremor with dopaminergic stimulation does not necessarily suggest that the condition is not Parkinson disease. Thus, for tremor-predominant Parkinson disease, the off/on test is less helpful.
Other clinical or historical features that support the diagnosis of Parkinson disease include the presence of a levodopa-induced dyskinesia, anosmia, and the presence of REM sleep disorder.
Some symptoms or clinical findings make the diagnosis of Parkinson disease less tenable. These may be symptoms that are occurring too early in the course of normal Parkinson disease, such as multiple falls or rapid progression of gait to the point of inability to walk within the first 5 years or severe dysphonia, dysarthria, or dysphagia early in the disease. Marked orthostatic hypotension or severe urinary incontinence early in the disease or the absence of any progression of motor symptoms for more than 5 years also make the diagnosis less likely. There are symptoms or signs that coexist with parkinsonian features that suggest a disease other than Parkinson disease. Cerebellar dysfunction, supranuclear gaze palsy, especially downgaze, progressive aphasia, cortical sensory loss, or limb apraxia all suggest a different diagnosis.
A Movement Disorders Society Task Force published a set of clinical diagnostic criteria for the diagnosis of Parkinson disease that takes into account all these factors.
While the diagnosis of Parkinson disease can be made on clinical grounds and in the majority of patients, some situations arise in which another form of testing can be helpful. A DaTscan or skin biopsy to evaluate for misfolded alpha-synuclein can be helpful in certain circumstances. The situations in which these tests might be helpful include patients with a prominent essential tremor and patients with significant tremor at rest and with action in whom a diagnosis of Parkinson disease versus essential tremor is unclear. Patients with early or very subtle symptoms, patients who show little improvement in their symptoms with dopaminergic stimulation, patients with less common parkinsonian symptoms such as “lower body” parkinsonism, and patients who develop parkinsonian symptoms in the setting of being on a potential dopamine-blocking drug all may be further assessed using these modalities.
DaTscan
The DaTscan is performed by intravenous injection of a radioligand, ioflupane, which binds to the presynaptic dopamine transporter protein. Single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging of the radioligand is done, which images the activity in the caudate and putamen. The images can show lower striatal metabolism and binding potential in patients with parkinsonian disorders that are caused by a presynaptic lesion (decreased amounts of dopamine). In one study looking at patients with uncertain diagnoses, the DaTscan changed the pretest diagnoses of almost 40% of the patients and resulted in a change in medication therapy in 70%. To date, the DaTscan has not been used to differentiate Parkinson disease from progressive supranuclear palsy or multiple systems atrophy (which also have abnormal DaT scans), but advances in imaging may allow that in the future.
Alpha-synuclein Seed Amplification Assays
Seed amplification assays are a group of techniques that detect protein misfolding in proteinopathies. Some of these techniques are already accepted for demonstrating prions in the diagnosis of Creutzfeldt-Jakob disease. Similar protein amplification assays have been developed to detect misfolded alpha-synuclein in biopsy material. The assays have been performed on cerebrospinal fluid, skin biopsies, and olfactory mucosa. Because the test is sensitive to alpha-synucleinopathies, it can differentiate between Parkinson disease and Lewy body disease (alpha-synucleinopathies) and progressive supranuclear palsy (tauopathy) or between Lewy body disease and Alzheimer disease.
Because these studies detect a biomarker, they may be able to diagnose parkinsonian conditions prior to the patient developing clinical signs. This potential ability to diagnose these diseases earlier will be important in the development of potential future therapies affecting disease progression.
PATHOLOGY
The pathologic hallmark of Parkinson disease is depigmentation of the substantia nigra and locus coeruleus with neuronal loss in the pars compacta of the substantia nigra. Both apoptosis and autophagy are involved in the process. Neuronal loss is also seen in the basal nucleus of Meynert and the dorsal motor nucleus of the vagus nerve. In affected areas, Lewy bodies, which are eosinophilic cytoplasmic inclusion bodies containing alpha-synuclein, are noted. The primary cause of Parkinson disease remains unclear. How Lewy bodies are specifically related to the progression of the disease is not known. Current theories of how neuronal loss occurs in Parkinson disease include mitochondrial dysfunction, inflammation, abnormalities in protein handling, and oxidative stress ( Figure 14.1 ).
PHARMACOLOGIC TREATMENT
The decision of when to treat a patient with Parkinson disease is made in collaboration with the patient. When symptoms affect the patient’s quality of life (the ability to work or socialize), treatment is started. There is no compelling evidence that starting treatment early has any impact on the progression of the disease, and no treatment confers neuroprotection. The decision to treat is based on the impact of symptoms.
Levodopa was the first effective medication for Parkinson disease and is still the most potent. Virtually all patients will use levodopa at some point during their disease. It is the immediate precursor to dopamine, which can cross the blood-brain barrier. It allows the depleted number of dopaminergic neurons to produce more dopamine and alleviate symptoms. It is usually paired with carbidopa, which blocks metabolism of levodopa in the periphery, increasing central nervous system bioavailability and lessening peripheral side effects, particularly nausea. Other side effects include hallucinations, delusions, somnolence, dystonia, and, prominently, dyskinesias. Dyskinesia (involuntary writhing movements) often limits the dose of carbidopa levodopa that can be used. Dyskinesias are estimated to occur in up to 40% of Parkinson disease patients within 4–6 years of starting carbidopa levodopa. For this reason, some practitioners will delay the use of carbidopa levodopa in favor of other agents (dopamine agonists), especially in younger patients. However, dopamine agonists are associated with a number of other unwanted side effects that will be described later in this chapter. Also, dopamine agonists are significantly less potent in ameliorating symptoms of Parkinson disease, and patients may sacrifice a better quality of life earlier in the disease in hope of putting off the onset of dyskinesias. Therefore, the decision of when to use carbidopa levodopa is made taking into account patient’s age and symptom complex and, potentially, the effectiveness of other agents on their symptoms by medication trial. A number of controlled-release formulations of carbidopa levodopa using both short-acting and controlled-release carbidopa levodopa have been developed as well as a system of infusing carbidopa levodopa gel into the jejunum through a jejunal tube and a pump as a means of minimizing motor fluctuations and dyskinesias. The presence of motor fluctuations and dyskinesias are primary reasons why other medications or surgical interventions are considered.
Dopamine agonists (pramipexole, ropinirole, and rotigotine) stimulate dopaminergic receptors in the central nervous system, alleviating symptoms of Parkinson disease. While dopamine agonists improve symptoms, they are predictably less potent than levodopa. They are frequently used because they are less likely to cause dyskinesias, and they tend to have a longer half-life. The decreased risk of dyskinesias may be because they are less potent stimulators of the D2 receptors. The decreased specificity, in the way that they stimulate dopaminergic receptors, may be the cause of their increased risk of hallucinations, hypotension, somnolence (sometimes with sleep attacks), and leg edema and the risk of compulsive behaviors, such as compulsive sexual behavior, buying, or gambling. The risks of hypotension and hallucinations are higher in elderly patients, and it is prudent to try to use carbidopa/levodopa in the elderly, if possible, to avoid complications.
Catechol- O -methyl transferase inhibitors (entacapone) and monoamine oxidase aldehyde dehydrogenase B (MAO-B) inhibitors (rasagiline and selegiline) inhibit enzymes involved in the breakdown of levodopa and dopamine. They prolong the effect of carbidopa/levodopa. They may also increase the side effects of levodopa, specifically, hallucinations, dyskinesia, and nausea. In the case of the MAO-B inhibitors, there is a risk of interaction with multiple drugs, including antidepressants in terms of causing serotonin syndrome.
Anticholinergic medications (trihexyphenidyl and benztropine) are not effective in treating bradykinesia but may be effective in decreasing rigidity, dystonia, and tremor. In patients (generally younger ones) whose early disease manifestations are rigidity and tremor, these medications, even as the sole agent, may be effective. Side effects limit dosing and include dry mouth, dry eyes, urinary retention, memory issues, and hallucinations. These agents should be used with caution in the elderly.
Antipsychotics are sometimes necessary to treat the symptoms of hallucination and paranoid delusions that may occur in Parkinson patients. Traditional agents, such as haloperidol, increase parkinsonian symptoms. The best tolerated agents include quetiapine, clozapine, and pimavanserin. Depression is a frequent comorbid symptom in Parkinson disease. Treatment with tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, or serotonin reuptake inhibitors have all been used. Cognitive behavioral therapy has been reported to be helpful, but no large-scale trials have been done.
Table 14.1 lists commonly used medications for treatment of Parkinson disease.
| Medication | Supplied | Dosage | Comment |
|---|---|---|---|
| Dopaminergic Medication | |||
| Carbidopa/levodopa | Multiple immediate-release and controlled-release formulations. Gel preparation for jejunal infusion | Start at 25/100 TID, titrating dose and dosing interval to symptomatic relief | Most potent medication but with short half-life. Dyskinesias more common |
| Pramipexole | Immediate and extended release formulations | Start at 0.125 mg TID, increasing weekly based on clinical response to total daily target dose of up to 1.5–4.5 mg | Less fluctuation of efficacy but less potent than carbidopa/levodopa. May develop compulsive behaviors. Fatigue and marked drowsiness are noted frequently |
| Ropinirole | Immediate and extended release formulations | Start 0.25 mg TID with gradual increases based on clinical response to daily total dose of up to 24 mg | |
| Rotigatine | Transdermal patch | 2 mg patch daily, increase weekly based on clinical response, up to 8 mg/day | |
| COMT and MAO-B Inhibitors | |||
| Entacapone | 200 mg. Also supplied in combination drug with carbidopa/levodopa | Take with each dose of carbidopa/levodopa | COMT inhibitor |
| Rasagiline | 0.5 mg, 1 mg | Take 0.5–1 mg daily | MAO-B inhibitor. Contraindicated with multiple drugs because of potential serotonin syndrome |
| Selegiline | 1.25 mg, 5 mg | Take 5 mg daily, if tolerated increase to 5 mg BID | |
| Anticholinergics | |||
| Benztropine | 0.5, 1, and 2 mg | Starting with 0.5 mg BID, increase based on clinical response up to 2 mg TID | Use with caution in elderly patients. Dry mouth and urinary retention are side effects |
| Trihexyphenidyl | 2 and 5 mg | Starting at 2 mg QD, increase based on clinical response up to 2 mg TID | |
| Treatment of Hallucinations and Delusions | |||
| Quetiapine | 25, 50, 100, 200, 300, and 400 mg | Start at 25 mg QHS and increase based on clinical response. Doses earlier in the day may be necessary | Rarely need to go above 400 mg/day total dose |
| Clozapine | 25, 50, 100, and 200 mg | Start at 12.5 mg QD and increase based on clinical response up to 300–450 mg total daily dose | Close following of absolute neutrophil count is mandatory |
| Pimavanserin | 10 and 34 mg | 34 mg QD | |
| Amantadine | 100 and 137 mg (long acting) | Start at 100 mg daily. 100 mg. BID is usual dose. Long-acting form is 137 mg daily | Used to treat dyskinesia and has mild dopaminergic effect by inhibiting reuptake of dopamine |
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