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| Phenomenon | Description | Pathophysiology | Treatment strategies |
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| Motor fluctuations | | | |
| Wearing-off | Predictable earlier end-of-dose deterioration and reemergence of PD motor/nonmotor symptoms/signs before the next scheduled oral LD dose | Loss of SNc dopaminergic neurons resulting in reduction in LD internalization and production, storage, and physiological release of DA | Assess compliance with current treatment. Reduce the interval between LD doses. Increase LD doses, particularly the first one in the morning or those in the afternoon. Use CR-LD. Add or increase DA agonists. Add COMT inhibitors and/or MAO-B inhibitors. Consider SA, LCIG, or DBS |
| Delayed-on | Increased latency between taking an oral dose of LD and experiencing clinical benefit from it | Delayed absorption of LD in the proximal jejunum or across BBB because of large amount of dietary neutral AAs that compete with LD active transport, erratic gastric emptying, anticholinergic or dopaminergic drugs, and food per se | Adjust protein intake by avoiding it in the first part of the day or spreading it throughout the day. Take LD on an empty stomach or with a small snack. Treat constipation and reduce or stop anticholinergic agents. Eradicate Helicobacter pylori. Add soluble oral LD preparations. Consider SA, LCIG, or DBS |
| Partial-on | Partial response to an oral dose of LD | Reduced absorption of LD. See pathophysiology of delayed-on fluctuations | See treatment strategies for delayed-on fluctuations |
| No-on | Occasionally no response of PD symptoms/signs to an oral dose of LD | See pathophysiology of delayed-on fluctuations. Markedly reduced or absent absorption of LD | See treatment strategies for delayed-on fluctuations |
| On-off | Sudden and unpredictable fluctuations between on and off phases (Table 1) | Possible pharmacodynamic neuroplastic changes in striatal medium spiny neurons and the BG | See treatment strategies for wearing-off fluctuations |
| Dyskinesia | | | |
| Peak-dose dyskinesia | Involuntary movements at the time of the LD peak, which coincide with the best antiparkinsonian effect of LD | Loss of SNc dopaminergic neurons resulting in reduction in LD internalization and leading to greater amount of DA production by serotoninergic neurons. Neuroplastic changes in DA and GABA receptors and overactivity of glutamatergic NMDA receptors in the BG. Disinhibition of the MC and associated motor cortices | Fractionate LD doses (smaller amounts, more frequently). Switch CR-LD to regular LD. Add or increase long-acting DA agonists. Discontinue COMT or MAO-B inhibitors. Add amantadine or clozapine. Consider SA, LCIG, or DBS |
| Diphasic dyskinesia | Involuntary movements at the beginning and/or the end of LD effect | See pathophysiology of peak-dose dyskinesia | Reduce the interval between LD doses. Add or increase long-acting DA agonists. Add soluble or crushed oral LD. Consider SA, LCIG, or DBS |
| Square-wave dyskinesia | Involuntary movements throughout the entire duration of LD effect | See pathophysiology of peak-dose dyskinesia | See treatment strategies for peak-dose and diphasic dyskinesia |
| Dystonia | | | |
| Off phase dystonia, including early morning dystonia | Sustained involuntary and painful muscle contraction during the off phase and/or on awakening | See pathophysiology of wearing-off and delayed-on fluctuations. Short half-life of oral LD for early morning dystonia | See treatment strategies for motor fluctuations. Minimize off time. Add bedtime CR-LD or overnight doses of regular LD for early morning dystonia. Botulinum toxin injection. Add muscle relaxant drugs or benzodiazepines. Consider DBS |
| On phase dystonia | Sustained involuntary muscle contraction during the on phase. It may often accompany peak-dose or diphasic dyskinesia | See pathophysiology of peak-dose dyskinesia | See treatment strategies for peak-dose dyskinesias. Botulinum toxin injection. Add muscle relaxant drugs or benzodiazepines. Consider DBS |
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