Dyskinesias in levodopa‐carbidopa intestinal gel infusion era: New challenges, new features

Long-term chronic therapy with levodopa in Parkinson’s disease (PD) has been associated with the development of motor complications in the form of fluctuations and dyskinesias. At present, one alternative with proven benefit in clinical trials is the continuous intrajejunal infusion of levodopacarbidopa intestinal gel (LCIG; Duodopa; Abbvie). We recently identified 2 patients with advanced PD who, after 7-24 months with stable doses of LCIG, presented choreodystonic lower-limb levodopa-induced dyskinesias, resembling a biphasic pattern but occurring during optimal dopaminergic stimulation. We performed a full clinical study to determine their physiopathology. Patient 1 was a 47-year-old man with PD diagnosed 15 years before, and patient 2 was a 60-year-old man with a 14-year history PD (clinical description in Supplementary Material). Both presented motor fluctuations and peak-dose dyskinesias difficult to control, so LCIG treatment was initiated. Their treatment just before LCIG was 670 mg of levodopa equivalent doses (LEDD) and rasagiline in patient 1 and 900 mg LEDD, rasagiline, and amantadine in patient 2. Both patients achieved good clinical control with LCIG (840 and 846 mg/day of levodopa, respectively, without rasagiline or amantadine). None used extra doses. After 7 months and 2 years on LCIG, respectively, both patients reported dyskinesias in their lower limbs occurring 20-30 minutes after the morning dose. Both demonstrated high-stepping gait with hip flexion and walked with a marked heel-to-toe pattern (Video S1). Dyskinesias coincided with improvement in bradykinesia (ON-time), and greatly interfered with gait. Up-titration of the maintenance dose or administration of extra doses worsened the symptoms, whereas down-titration did nothing to improve them, disappearing only in the absence of medication. The description of methods is provided as Supplementary Material. As shown in Figure 1 and Table S1 (Supplementary Material), results of clinical assessment correlate with plasma levels of levodopa and doses administered. Clinical scores and results of the video assessment show that patients were in ON-state when experiencing these dyskinesias. All variables were significantly associated with doses and plasma levels of levodopa. Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores correlated with levodopa levels (correlation coefficient, -0.671). In these 2 patients, we demonstrated the presence of dyskinesias clinically similar to the biphasic type, but associated with levodopa benefit, and whose severity was correlated with levodopa levels in plasma. These patients initially responded to LCIG with improvement in established motor complications, but a markedly different pattern of dyskinesia occurred within a relatively short period. Biphasic dyskinesia and “silly walks” have been associated with low dopamine levels, not with ON-medication periods. It is generally considered that once dyskinesia is established, the same pattern of movements will be triggered by dopaminergic stimulation, which is not the case in this report. Possibly, this might be related to maladaptive plastic changes related to their previous long-term treatment and the extent and pattern of progressive nigral degeneration. Only 2 of the 30 patients with LCIG in our clinic developed this problem. Individual susceptibility might partly explain this. At present, patient 1 continues with the same treatment, as he tolerates his dyskinesias. Patient 2 underwent bilateral DBS surgery and has responded well. In conclusion, these cases suggest that continuous administration of levodopa in patients with advanced disease may develop drug-related dyskinesias with mixed characteristics of those described in the literature.