Levodopa, motor fluctuations and dyskinesia in Parkinson’s disease

Abstract

Parkinson's disease (PD) is one of the most frequent, chronic, progressive degenerative disorders of the CNS, characterised by altered neurotransmission of dopamine in the basal ganglia. This may result in disturbances of movement, mobility and posture symptoms, all of which cause severe disability in PD patients. There is no cure for PD. Current treatment approaches aim at symptomatic improvement with a balance of the altered neurotransmission, particularly in striatal dopaminergic neurons. Levodopa, the metabolic precursor of active dopamine, is the most effective compound in the drug treatment of PD. However, chronic exposure to levodopa and related dopaminergic agents supports an onset of movement behaviour fluctuations and dyskinesia in the long term. Dyskinesia is unwanted, sometimes excessive and causes abnormal facial, body and limb movements that appear in many PD patients who are often dependent on the overall dosage of dopaminergic substitution. This complication of anti-Parkinsonian drug therapy supports disability and reduces quality of life in PD patients and their caregivers. This review focuses on the major clinical features and knowledge on the aetiology of these treatment-associated, long-term side effects of dopaminergic drug treatment in PD. It also gives an overview of existing and potential future treatment-strategies for the management of these troublesome treatment complications that affect motor behaviour in PD patients.

Drug therapy in patients with Parkinson’s disease

“…Avoidance of LD implementation is known to postpone onset of MC. MC limit quality of life and cause caregiver burden considerably [26]. There is study based evidence that in the long term outcome quality of life does not differ much depending of which drug, levodopa or pramipexole, has been used for treatment initiation.…”

“…Loss of presynaptic dopaminergic autoreceptor function and other compensating abilities to avoid not physiologic high dopamine concentrations in the synaptic cleft are currently looked upon as the main central cause for MC appearance. Onset of MC is predominantly looked upon as the clinical consequence of the induction of frequent alternating postsynaptic dopamine receptor stimulation with further downstream intracellular changes in neuronal nigrostriatal cells, which regulate motor behaviour [26]. Continuous stimulation of these postsynaptic dopamine uptake sites may delay onset of MC, which often appear in combination with a wide array of non motor symptoms [28].…”

Valbenazine granted breakthrough drug status for treating tardive dyskinesia

“…Any kind of emotions may increase severity of hyperkinetic movement behavior [1]. They often disturb caregivers more than affected patients themselves [2]. Rapid and dance-like uncontrollable movements are commonly described as chorea or choreiform movements.…”

“…They may be invisible in the case of abdominal tensing or toe crunching. Onset of hyperkinetic movements may be a disease symptom, for instance Huntington's disease, or a result of drug treatment, for instance chronic and high L-DOPA dosing in patients with Parkinson's disease [2]. Blocking of dopamine receptors in the brain with typical neuroleptics or the antiemetic metoclopramide may induce onset of acute dystonia [3,4].…”

Gait disturbances in Parkinson disease. Did freezing of gait exist before levodopa? Historical review

“…In addition, motor and non-motor complications must also be taken into account. Motor complications include motor fluctuations and dyskinesias, which are associated to severity of PD but also to dopaminergic treatment [1][2][3][4]. Gait disturbances are very frequent in advanced PD and are occasionally seen early in the course of the disease [5][6][7].…”