Updates in the medical management of Parkinson disease
ABSTRACTMost, if not all, currently available drugs for Parkinson disease address dopaminergic loss and relieve symptoms. However, their adverse effects can be limiting and they do not address disease progression. Moreover, nonmotor features of Parkinson disease such as depression, dementia, and psychosis are now recognized as important and disabling. A cure remains elusive. However, promising interventions and agents are emerging. As an example, people who exercise regularly are less likely to develop Parkinson disease, and if they develop it, they tend to have slower progression.
KEY POINTS
- Parkinson disease can usually be diagnosed on the basis of clinical features: slow movement, resting tremor, rigidity, and asymmetrical presentation, as well as alleviation of symptoms with dopaminergic therapy.
- Early disease can be treated with levodopa, dopamine agonists, anticholinergics, and monoamine oxidase-B inhibitors.
- Advanced Parkinson disease may require a catechol-O-methyltransferase (COMT) inhibitor, apomorphine, and amantadine (Symmetrel). Side effects include motor fluctuations, dyskinesias, and cognitive problems.
More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.
This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.
PARKINSON DISEASE IS MULTIFACTORIAL
Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.
The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.
CARDINAL MOTOR SYMPTOMS
In general, Parkinson disease is easy to identify. The classic patient has1:
- Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
- Rigidity, which is felt by the examiner rather than seen by an observer.
- Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
- Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.
Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.
NONMOTOR FEATURES CAN BE MORE DISABLING
Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.
Fatigue is very common and, if present, is usually one of the most disabling features.
Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.
INCREASINGLY PREVALENT AS THE POPULATION AGES
Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:
- 10 to 20 years: juvenile-onset
- 21 to 40 years: young-onset.
Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.2 More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.
DIAGNOSIS IS STILL MAINLY CLINICAL
The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.3
Imaging useful in select patients
The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.
The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.
Check for Wilson disease or brain tumors in young or atypical cases
For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.
For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.
Consider secondary parkinsonism
Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:
- Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
- Strokes in the basal ganglia
- Normal pressure hydrocephalus.
Parkinson-plus syndromes
Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.
Parkinson-plus syndromes include:
- Progressive supranuclear palsy
- Multiple system atrophy
- Corticobasal degeneration
- Lewy body dementia.
Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).4
