Classification of fluctuations in patients with Parkinson's disease.

Patients with Parkinson's disease (PD) are subject to a wide range of fluctuations in their clinical state, most of them treatment-related but some more disease-related. Short-duration motor fluctuations include freezing and paradoxic kinesis, lasting seconds to minutes. It is important to distinguish between "off" period freezing, which may be helped by measures to increase time "on," and freezing that is present in both "on" and "off" periods, which is difficult if not impossible to treat. Medium-duration fluctuations associated with chronic L-dopa treatment include wearing-off and "on-off" responses, which can involve (a) return of parkinsonism, (b) dyskinesias, and (c) non-motor fluctuations. A poorly understood long-duration pharmacodynamic response to L-dopa lasting up to 2 weeks may also be seen. This may manifest as late deterioration after L-dopa is withdrawn. More importantly, and more commonly, it is important to recognize that the ultimate effect of an alteration in L-dopa treatment may take 2 weeks to equilibrate in the brain. "Optimization" of L-dopa therapy is therefore not a realistic expectation during an inpatient admission and is instead primarily a long-term outpatient procedure. The "off" state is not the same as untreated PD, and may represent rebound worsening after the beneficial effect of L-dopa has worn off. Sometimes there is also transient worsening at the onset of effect of a dose. "Off' period dyskinesias tend to be relatively fixed, painful, and dystonic. Biphasic (beginning and/or end of dose) dyskinesias are often severe, ballistic, and stereotypic. Peak dose or "square wave" dyskinesias comprise a mix of mobile dystonia or chorea that is usually painless. Many patients experience any combination of panic, anxiety, and depression in their "off" periods, and many also experience pain, with instant relief as they turn "on." Other parameters that may vary between the "on" and "off" states include urinary and bowel dysfunction, blood pressure, respiratory function, and sweating attacks. Most but not all of these phenomena can be related to a simplistic but nevertheless usually practically useful model of differing levels of central dopaminergic stimulation. In difficult cases, an acute apomorphine challenge analogous to the effects of a "Tensilon test" in myasthenia gravis may help to determine whether a given clinical feature represents over- or understimulation of central dopamine receptors.