ABSTRACT
IntroDuCtIon: ClInICAl FeAtureS AnD PAthoPhySIologyIn 1817, British physician James Parkinson published a manuscript describing what he termed the “shaking palsy” [1]. This treatise was based on his observation of six cases, some of whom were seen as patients and some whom were casually observed in the street. Dr. Parkinson’s was the first well-formulated description of the four cardinal features of what has come to be known as Parkinson disease (PD): resting tremor, bradykinesia, rigidity, and gait disturbance. The resting tremor of PD tends to improve when a patient holds out his or her arms or during active movement and tends to worsen during mental distraction. Parkinsonian bradykinesia refers not only to the slowness of movement but also to a decrement in amplitude of movement. It is often assessed by having a patient attempt to rapidly tap
fingers or open and close the hand. Rigidity is an increase in tone during passive movement and usually includes a rachet-like “cogwheeling.” Gait disturbance includes both bradykinetic components, such as a stooped posture, shuffling steps with shortened stride length, and reduced arm swing, as well as a postural instability component, which may lead to falls.By the 1920s, neuropathological studies revealed that degen-eration of the pigmented neurons within the substantia nigra pars compacta was a hallmark of disease [2]; however, it was not until 1960 that striatal dopamine depletion was definitively demon-strated in PD [3]. This discovery soon led to attempts at dopamine replacement, beginning with administration of levodopa, the bio-chemical precursor to dopamine [4]. Dramatic improvements in motor parkinsonism were seen, and in 1969 a double-blind placebo controlled trial was published establishing levodopa as a highly effective therapy in PD [5].The initial excitement over the discovery of levodopa’s effects was somewhat tempered by the later realization that, with advancing PD, other motor complications often develop [6]. These include motor fluctuations, most often experienced as a wearingoff of the levodopa effect between doses. In severe cases, patients may need to take levodopa at intervals as short as every 90 minutes to maintain consistent motor effects. In addition to experiencing fluctuations, patients on levodopa may develop drug-induced dyskinesias which are choreiform “squirmy” movements of the face, neck, truck, or limbs. Dyskinesias usually occur at the time of peak levodopa serum levels, about 20-40 minutes after oral administration. Patients with both motor fluctuations and dyskinesias often cycle between each dose, “yo-yoing” between a medication-OFF state with poor movement, a dyskinetic state with excessive movement, and a well-treated state.In an attempt to address motor complications, additional classes of medication, such as catechol-O-methyl transferase inhibitors, monoamine oxidase type B inhibitors, and dopamine agonists have been introduced [7]. While these may be somewhat helpful, as PD advances patients’ fluctuations and dyskinesia may not be adequately addressed with medical therapy alone. However, it is important to realize that even in advanced PD, levodopa is still very effective during the so-called medication-ON time.
