Unmasking levodopa resistance in Parkinson's disease.

Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine-sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose-limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several nonmotor features (eg, specific cognitive functions), the response to levodopa is fairly complex, with a combination of levodopa-responsive, levodopa-resistant, and even levodopa-induced characteristics. A possible explanation relates to the mixed presence of underlying dopaminergic and nondopaminergic brain lesions. We suggest that clinicians take these possibilities into account before concluding that symptoms or signs of PD are totally levodopa resistant.