Motor fluctuations in Parkinson's disease

Motor fluctuations are variations in motor performance in relation to levodopa dosing, appearing after several years of levodopa use as the disease advances.

Pathy's describes three patterns: a delayed effect of levodopa ("delayed on"), wearing-off between doses, and the on–off phenomenon.

Essentials describes the same clinical spectrum as morning akinesia, peak-dose dyskinesias and freezing episodes, collectively termed the on–off phenomenon.

Fluctuations are accompanied by involuntary movements — chorea, athetosis and dystonia (peak-dose dyskinesia, diphasic dyskinesia and off-period dystonia).

In advanced PD (after 10–15 years), fluctuations and motor dyskinesia are very frequent and remain a challenge for treatment.

Central mechanism: progressive nigrostriatal degeneration reduces the striatal capacity to store and buffer dopamine, so the clinical effect increasingly follows the short plasma half-life of levodopa, producing pulsatile rather than tonic receptor stimulation.

Peripheral mechanism: gastric emptying is delayed in at least 70% of PD patients attending neurological clinics, even without levodopa therapy, and levodopa slows it further.

Levodopa retained in the stomach is metabolised to dopamine and becomes unavailable for systemic absorption, contributing to nausea, bloating and impaired nutrition.

In patients with the on–off phenomenon, gastric emptying may normalise during the "on" phase; conversely, variation in the rate of emptying causes erratic levodopa absorption and thereby contributes to the on–off phenomenon — a two-way relationship.

Dietary protein competes with levodopa for absorption, which is why standard levodopa is given 30 minutes before meals.

Constipation is associated with reduced efficacy of medication due to reduced absorption, and occurs in about half of PD patients.

Take a patient or carer diary of on and off periods, mapped against dose times and meals; review total daily levodopa, dose interval, formulation and adherence.

Exclude reversible contributors: constipation, intercurrent infection, dehydration, malabsorption, protein timing, and drugs that antagonise dopamine (metoclopramide, neuroleptics).

Look specifically for early-morning akinesia, early-morning and off-period dystonia and freezing, since each has a different solution.

First step: revise the timing of levodopa administration. Fractionate the same total dose into smaller, more frequent doses to reduce peak-dose dyskinesia and shorten off periods.

Dispersible Madopar achieves peak plasma concentration faster and is used for early-morning akinesia, allowing the first standard dose to be taken at the same time.

COMT inhibitors (entacapone, tolcapone) decrease dopamine degradation and increase and prolong the levodopa effect — they are useful in older patients with motor fluctuations and/or levodopa-induced dyskinesia.

Stalevo (levodopa/carbidopa 50/12.5, 100/25 or 150/37.5 mg with fixed entacapone 200 mg) is indicated for patients with end-of-dose fluctuation not stabilised by levodopa–decarboxylase inhibitor alone.

Amantadine 200–400 mg/day is effective in lessening peak-dose dyskinesia. Adjust the dose in renal impairment; delirium is frequent in old patients.

Direct duodenal infusion of levodopa is advocated as a solution to erratic gastric absorption; increasing the decarboxylase-inhibitor to levodopa ratio has also been proposed. Subcutaneous apomorphine infusion has limited data but shows benefit, including for swallowing.

Bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus interna produces sustained improvement in motor function, especially for levodopa-responsive symptoms, and reduces drug-induced involuntary movements. It is offered to cognitively intact patients with severe disability from motor complications refractory to best medical treatment; severe comorbidity is a limitation. Pathy's notes that efficacy in patients over 70 is similar to that in younger patients, with no age-related increase in adverse effects, but that disability continues to progress because neurodegeneration continues.

Rehabilitation sessions should be held at the time of the peak effect of levodopa to maximise participation.

Manage constipation actively (hydration, fibre, macrogol, psyllium) because it both worsens absorption and causes nausea and anorexia; entacapone-induced diarrhoea can be turned to advantage.