Patients with late stage Parkinson’s disease (PD) develop several motor and non-motor complications, which dramatically impair their quality of life. These complications include motor fluctuations, dyskinesia, absent or unpredictable response to medicines, falls, dysautonomia, dementia, hallucinations, sleep disorders, depression, and psychosis.
Despite a short plasma half-life of approximately one hour, levodopa’s duration of action can last days, independent of plasma concentration. However, the duration of effect reduces (to hours at most) as the disease progresses; a phenomenon strongly linked to the loss of slowly evolving postsynaptic pharmacodynamic changes in the central nervous system (CNS), rather than the plasma concentration at this stage. Patient mobility may fluctuate throughout the day due to dopaminergic stimulation being either inadequate (off-periods) or excessive (peak dose dyskinesia).
Common Motor Fluctuations
(a) Akinesia (motor blocks and freezing) are the most debilitating symptoms of PD. At times, a patient can experience a total loss of movement which may involve hesitation when beginning to walk (start hesitation), or sometimes a sudden inability to move the feet during specific situations, such as turning or crossing busy streets, contributing to falls. Five subtypes of freezing motor blocks are: “start hesitation”, “turn hesitation”, “hesitation in tight quarters”, “destination hesitation” and “open space hesitation”.
(b) Morning akinesia (delayed onset of response to first daily dose) may occur due to delayed gastric emptying (gastroparesis), impaired intestinal absorption, pharmacodynamic effects, or other mechanisms which are common in PD and are best managed using strategies to enhance levodopa absorption.
(c) Early morning dystonias are an abnormal tonicity of muscle, characterised by prolonged, repetitive muscle contractions (spasms) that may cause twisting or jerking movements of the body or a body part.
(d) “Off” periods (drug resistance) result from the failure of a dose to induce an “on” period and are often due to gastroparesis.
(e) Diphasic dyskinesia (dyskinesia-improvement-dyskinesia [D-I-D] pattern response): Patients experience dyskinetic symptoms lasting up to half an hour before the levodopa takes effect and dopamine receptors are “switched on”. Patients then express no symptoms as the medicine is metabolised, and will again experience over an hour of dyskinetic symptoms after the medicine wears off. There is no one remedy for the “D-I-D response”.
(f) Peak dose dyskinesia (improvement-dyskinesia/dystonia-improvement [I-D-I] pattern response): Involuntary movements of the limbs or trunk occur, usually when the plasma levels of levodopa are maximal (peak dose dyskinesia).
(g) On/off phenomenon (random oscillations/fluctuations) are an almost invariable consequence of sustained levodopa treatment, characterised by phases of immobility and incapacity associated with depression, alternating with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis.
(h) End of dose dystonia (wearing off) causes painful twisting and cramping of the feet or legs at the end of a dose cycle, such as early in the morning. This is due to inadequate dopaminergic stimulation.
(i) Myoclonus: Sudden, rapid and brief involuntary jerking of muscles or parts of muscles, without any rhythm or pattern, occurring due to various brain disorders.
(j) Akathisia: Motor restlessness ranging from a feeling of inner disquiet, often localised in the muscles, to an inability to sit still or lie quietly. This is a relatively common side effect of antipsychotics, antidepressants (SSRIs), metoclopramide, some calcium channel blockers, dopamine agonists, amphetamine, and buspirone.Symptoms of akathisia are both objective and subjective. Objective symptoms involve movements which usually take the form of shuffling of feet while sitting, and pacing or rocking while standing. Subjective symptoms are feelings of dysphoria that include tension, panic, irritability and impatience.
Therapeutic management should have the objective of creating a balance between the benefits and adverse effects of the pharmacological treatments available.
Manipulating the timing and/or dose of medicines can improve motor control, from administering larger and less frequent dose increments, to reducing and overlapping doses (e*). Absorption can be enhanced by crushing or chewing the tablets, using a dispersible formulation, and taking the dose on an empty stomach with a full glass of water (b, d). Using a slow release formulation can extend the duration of action, particularly overnight (d).
Levodopa plasma levels can be adjusted to improve motor control throughout the day using strategies such as introducing slow release preparations, especially for the last dose at night to protect against nocturnal “off-periods” or early morning akinesia (h). They are less effective in treating daytime motor fluctuations. Supplementation with a “kick-start” from a rapid release formulation can prevent morning dystonias (b). Levodopa levels can also be maintained with smaller, more frequent, doses by introducing oral solutions, or continuous duodenal (gel) or intravenous infusions (b, c, d, f, g, h). Alternatively, adding a catechol-O-methyl transferase (COMT) inhibitor (e.g. entacapone) will inhibit the metabolism of levodopa to preserve plasma levels (e, g, h). Decreasing the night-time levodopa dose is recommended for managing myoclonus (i).
Dopaminergic alternatives can augment the dopaminergic effect of levodopa. Gradually introduce or increase a dopamine agonist (e.g. bromocriptine), while potentially reducing the levodopa dose (a, b, c, d, f, g, j). Alternatively, add a longer half-life dopamine agonist, preferable in younger patients (e.g. pergolide, pramipexole, ropinirole or cabergoline). The parenteral dopamine agonist, apomorphine, may be administered subcutaneously as intermittent injections or by continuous infusion (d, g).
Adjuvant medicines, such as amantadine, propranolol, fluoxetine, buspirone or clozapine, may be considered. Amantadine can cause nightmares, anticholinergic adverse effects and livedo-reticularis, a skin condition. It should be avoided in patients with hallucinations or dementia. If used, the last dose should be given before mid-afternoon (j).
Also consider adding: monoamine oxidase (MAO)-B inhibitors (e.g. rasagiline, selegiline), benzodiazepine (e.g. clonazepam) (i, j), baclofen (which should be carefully introduced to avoid aggravation) (c), or gabapentin (j). Anticholinergic medicines may be added or reduced (e), and botulinum toxin may be used for selective denervation (c).
The adjuvant drugs recommended for the management of end-of-dose dystonias (h) reduce the “off time”, the levodopa dose, and improve Unified Parkinson Disease Rating Scale scores, but at the cost of increased dyskinesias and numerous other side effects.
Non-drug and other adjunctive managements that may be considered include deep brain stimulation (d, e, g) or a drug holiday (g). Regular exercise and shedding excess weight are useful during the early stages of the disease to maintain good muscle tone and reduce any impediments to movement other than those caused by the disease.
Stereotactic functional neurosurgery is very effective in younger patients with severe motor fluctuations that do not have obvious cognitive impairment, and are poorly controlled with medicines. Assessment by a movement disorder specialist, with or without neuropsychological assessment, is recommended prior to referral to a neurosurgeon.
Supportive care, including physical and rehabilitative interventions by allied health professionals have key roles in the later stages of disease. Physiotherapists and occupational therapists can assist in: developing gait modifications (e.g. tapping, rhythmic commands, stepping over objects and rocking), balance retraining, providing instructions regarding compensatory strategies which emphasise the use of external cues to help initiate movement, or how to break down complex movements into simpler sequences. Speech therapists can improve speech clarity and volume, and alleviate swallowing difficulties through careful assessment and treatment. Dietitians can provide useful guidance, particularly to reduce intake of protein and antacids (b), which may affect the pharmacokinetics of medicines. Hence, it is imperative to have an integrative approach in managing motor complications in late stage Parkinson’s Disease.
* The italicised letters within brackets within the beginning of this article refer to the Common Motor Fluctuations discussed further in the article.
- A J Lees. The on-off phenomenon. Journal ofNeurololy, Neurosurgery andPsychiatry. Jun 1989; 52(Suppl): 29–37.
- Annals of Indian Academy of Neurology. Treatment in late Parkinson’s disease; Jul 2011; 14(Suppl1): S11–S13.
- B R Thanvi, T C N Lo, D P Harsh. Psychosis in Parkinson’s disease. Postgrad Med J 2005; 81: 644-646 doi:10.1136/pgmj.2004.032029
- Barbato L, Stocchi F, Monge A, Vacca L, Ruggieri S, Nordera G, Marsden CD.The long-duration action of levodopa may be due to a postsynaptic effect. ClinNeuropharmacol. 1997 Oct; 20(5): 394-401.
- ChristoferLundqvist. Continuous levodopa for advanced Parkinson’s disease. Neuropsychiatr Dis Treat. Jun 2007; 3(3): 335–348
- Friedman JH, Factor SA. Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease. MovDisord 2000; 15:201-11.
- Hely MA, Fung VSC, Morris JGL. Treatment of Parkinson’s disease. J ClinNeurosci 2000; 7: 484-94.
- Hill MP, Bezard E, Brotchie JM, et al. The antiepileptic, levetiracetam (Keppra), modulates the process of priming for L-dopa-induced dyskinesia in MPTP-lesioned marmosets. European J Neurology. 2003;10: 164
- Joseph Jankovic and L Giselle Aguilar. Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat. Aug 2008; 4(4): 743–757. Published online Aug 2008. PMCID: PMC2536542.
- Joseph Jankovic y Eduardo Tolosa. Therapeutic Strategies in Parkinson’s disease. Parkinson’s disease and movement disorders. Lippincott Williams & Wilkins. 5th Edition, 2002; 116-152.
- Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow-up. J NeurolNeurosurg Psychiatry. 1998;65:709–16
- Sara Varanese, Zoe Birnbaum, Roger Rossi, and Alessandro Di Rocco. Treatment of Advanced Parkinson’s disease. Parkinsons Dis. 2010; 2010: 480260. Published online Feb 7, 2011. doi:10.4061/2010/480260
- Stuart H Isaacson, K Ray Chaudhuri. Morning Akinesia and the Potential Role of Gastroparesis – Managing delayed Onset of First Daily Dose of Oral Levodopa in Patients with Parkinson’s disease. European Neurological Review, 2013;8(2): 82–4
- V.S.C. Fung, M.A. Hely, Department of Neurology, G. De Moore, Department of Psychiatry and J.G.L. Morris, Department of Neurology, Westmead Hospital, Westmead, New South Wales. Drugs for Parkinson’s disease. Australian Prescriber 2001; 24 :92-5
- VerhagenMetman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease.Neurology. 1998 May; 50(5): 1323-6.