This has been a boom year for Parkinson disease, with the US Food and Drug Administration (FDA) approving two new therapies, and with others in the pipeline.
This article details clinical signs of Parkinson disease, discusses functional imaging, provides an update on current thinking on disease pathogenesis, and gives an overview of managing parkinsonian symptoms and dyskinesias.
DIAGNOSIS REMAINS CLINICAL
Although a better understanding of Parkinson disease has been gained in recent years, with the recognition of several premotor features and potential biomarkers, its diagnosis is still primarily based on clinical motor findings. The four cardinal motor features have the mnemonic TRAP:
- Tremor at rest can be subtle, involving just the thumb, best observed when the patient is sitting with the hand resting on the lap; or it can be obvious, involving the entire hand, arm, feet, lips, and chin.
- Rigidity can be felt rather than seen, by slowly passively rotating the patient’s wrist or elbow and feeling resistance. The right and left sides often differ.
- Akinesia or bradykinesia (slowness or lack of movement) can be observed by having the patient walk down a hallway. One may observe reduced arm swing and hesitation in initiating movement.
- Postural instability usually develops later rather than sooner in the disease progression. The patient may need to hold onto someone to maintain balance when getting up or walking.
At least two features must be present to make the diagnosis of parkinsonism. One feature must be tremor or rigidity.
Although the criteria for parkinsonism appear simple, the diagnosis of Parkinson disease is not always clear-cut. For example, shaking can be secondary to a dopamine receptor-blocking medication, to anxiety, or to essential tremor; rigidity and slowness may be due to arthritis; and postural instability can result from a neuropathy. Moreover, other neurodegenerative parkinsonian disorders may respond to levodopa (at least initially) and may present with levodopa-induced dyskinesias. Robust response to levodopa and the occurrence of dyskinesias are two additional features that strongly suggest the diagnosis of Parkinson disease.
Supporting parkinsonian features include stooped posture, masked facies, micrographia (small handwriting), drooling, speech changes (eg, hypophonia or soft speech, stuttering, slurring, monotonic speech), and a shuffling, festinating gait (quick short steps as if falling forward).
Parkinsonism is a broader term than Parkinson disease or idiopathic Parkinson disease. It is characterized by akinetic rigidity and impaired motor activity that leads to reduced function and falls; behavioral changes also may occur.
In the United States, Parkinson disease is the most common cause of parkinsonism. Other nonneurodegenerative causes are drug-induced parkinsonism (due to dopamine receptor antagonists such as antipsychotic or antiemetic drugs), stroke (in the basal ganglia or frontal lobe), and normal-pressure hydrocephalus (causing lower-body parkinsonism). Mimics of parkinsonism include essential tremor and psychogenic parkinsonism.
Parkinsonism can also be caused by Parkinson-plus disorders, ie, neurodegenerative conditions characterized by parkinsonism along with additional signs and symptoms, as listed below. Parkinson-plus disorders include progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Lewy body disease.
Clinical features that suggest a diagnosis other than Parkinson disease include1:
- Poor response to adequate dosages of levodopa
- Early onset of postural instability and falls
- Axial rigidity (eg, stiff neck) more than appendicular rigidity
- Early dementia
- Supranuclear gaze palsy
- Unusual movements besides tremor, eg, limb dystonia, myoclonus, limb levitation or alien limb syndrome
- Profound autonomic dysfunction
- Psychotic symptoms before taking levodopa or dopaminergic medication.
The precise diagnosis of Parkinson-plus disorders is not critical, as the treatment is generally the same for all of them: ie, levodopa (if it shows some efficacy and is well tolerated), with additional symptomatic treatment for features such as depression, cognitive impairment, and autonomic dysfunction, and supportive therapy including physical, occupational, speech, and swallowing therapy.
IMAGING MAY ASSIST IN THE DIAGNOSIS
Dopamine transporter single-photon emission computed tomography (SPECT) is a functional imaging technique that supposedly reflects dopamine uptake by surviving presynaptic dopaminergic neurons in the striate bodies of the basal ganglia. Normal uptake shows distinct cashew-shaped enhancement bilaterally. In Parkinson disease, the enhanced areas are smaller and asymmetric, first with diminution of the tail (representing the putamen), then later involving the head (representing the caudate) along with the other striate bodies (Figure 1).
Dopamine transporter SPECT does not distinguish one neurodegenerative parkinsonian disorder from another. Therefore, it should not be used to distinguish Parkinson disease from other Parkinson-plus syndromes. But it does distinguish neurodegenerative parkinsonian disorders from nonneurodegenerative conditions and mimics, which have a normal result on dopamine transporter SPECT (Table 1).
SLOWING DISEASE PROGRESSION
Current treatments for Parkinson disease can significantly improve symptoms but, unfortunately, do not cure the disease or slow its progression. Testing whether agents modify the disease course is particularly difficult with Parkinson disease, because it affects individuals differently, has a wide spectrum of symptoms, has a long time course, and lacks definitive markers to monitor progression. Some agents have shown promise:
Caffeine. People who drink coffee are less likely to develop Parkinson disease, with the risk declining with the number of cups per day.2 For those who have the disease, drinking coffee is associated with reduced symptoms.
Exercise improves Parkinson disease and may prevent it, and some studies suggest that it can delay its progression.3 Exercise has been shown in an animal model to reduce the vulnerability of dopamine neurons to the toxic agent 6-hydroxydopamine.4 Functional magnetic resonance imaging studies have shown blood flow patterns before and after exercise that are similar to those seen in patients with and without Parkinson medication.3
Rasagiline, a monoamine oxidase B (MAO-B) inhibitor used for symptomatic treatment of Parkinson disease, had conflicting results in a neuroprotective clinical trial. Patients who received rasagiline 1 mg daily—but not those who received 2 mg daily—at the beginning of the trial had better Parkinson motor scores compared with patients who received rasagiline 9 months later.5
Inosine is a urate precursor that elevates urate levels in serum and the central nervous system. For unknown reasons, patients with Parkinson disease tend to have a low uric acid level, and higher levels are associated with milder disease. It is hoped that raising the uric acid level to a “pre-gout level” may slow the progression of Parkinson disease.
Isradipine, a calcium channel blocker, was found in an epidemiologic study of elderly patients to be associated with reduced likelihood of developing Parkinson disease.6 The drug is now undergoing clinical trials.
Smoking. Although cigarette smokers have long been recognized as having a very low risk of developing Parkinson disease, smoking is not recommended.
Agents found ineffective. Agents that have been tested and found ineffective in modifying the course of Parkinson disease include vitamin E, coenzyme Q10, riluzole, GPI-1485, pramipexole, cogane, CEP-1347, TCH-346, and creatine.