Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites. See the images below.
Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
Signs and symptoms
Initial clinical symptoms of Parkinson disease include the following:
Subtle decrease in dexterity
Decreased arm swing on the first-involved side
Decreased facial expression
Rapid eye movement (REM) behavior disorder (RBD; a loss of normal atonia during REM sleep)
Decreased sense of smell
Symptoms of autonomic dysfunction (eg, constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis)
A general feeling of weakness, malaise, or lassitude
Depression or anhedonia
Slowness in thinking
Onset of motor signs include the following:
The most common initial finding is a resting tremor in an upper extremity
Over time, patients experience progressive bradykinesia, rigidity, and gait difficulty
Axial posture becomes progressively flexed and strides become shorter
Postural instability (balance impairment) is a late phenomenon
The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at or shortly after diagnosis.
Symptomatic and neuroprotective therapy
Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective (disease modifying) therapy. At this time, there is no proven neuroprotective or disease-modifying therapy.
Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI), remains the gold standard of symptomatic treatment for Parkinson disease. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation, allowing for greater levodopa distribution into the central nervous system. Levodopa provides the greatest antiparkinsonian benefit for motor signs and symptoms, with the fewest adverse effects in the short term; however, its long-term use is associated with the development of motor fluctuations (“wearing-off”) and dyskinesias. Once fluctuations and dyskinesias become problematic, they are difficult to resolve.
Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment of early disease. These drugs provide mild symptomatic benefit, have excellent adverse effect profiles, and, according to a Cochrane review, have improved long-term outcomes in quality-of-life indicators by 20-25%.
The cornerstone of symptomatic treatment for Parkinson disease (PD) is dopamine replacement therapy. The criterion standard of symptomatic therapy is levodopa (L-dopa), the metabolic precursor of dopamine, in combination with carbidopa, a peripheral decarboxylase inhibitor (PDI). This combination provides the greatest symptomatic benefit with the fewest short-term adverse effects.
Dopamine agonists such as pramipexole and ropinirole can be used as monotherapy to improve symptoms in early disease or as adjuncts to levodopa in patients whose response to levodopa is deteriorating and in those who are experiencing fluctuations in their response to levodopa.
Monoamine oxidase (MAO)-B inhibitors inhibitors such as rasagiline and selegiline provide symptomatic benefit as monotherapy in early disease and as adjuncts to levodopa in patients experiencing motor fluctuations.
Catechol-O -methyl transferase (COMT) inhibitors inhibitors such as entacapone and tolcapone may be used to increase the peripheral half-life of levodopa, thereby delivering more levodopa to the brain over a longer time.