Patients with mid- to late-stage Parkinson’s disease can develop motor complications, including symptom fluctuations and isokinetic disorders, as a result of long-term anti-levodopa drugs. Foreign literature reports that the incidence of symptom fluctuations after 4-years of levodopa treatment is 12-60% and the incidence of isokinetic disorders is 8-64%. For motor complications that cannot be improved by adjusting the drug dose and number of doses, deep brain electrical stimulation surgery can be considered.
I. Heterokinesia
Heterokinesia, also known as dyskinesia, is characterized by involuntary dance-like, throwing-like movements of the head, face, limbs or trunk, as well as dystonia-like movements. It usually appears after 5 years of medication and is related to the dose of the medication. It often occurs when the dose of medication of methyldopa or benzodiazepine reaches more than 3 tablets, because the patient feels much more comfortable with mild agitation compared with rigidity or continuous tremor, and there is no damage to the body.
There are three common clinical types of athetoid disorders.
1. Dose peak isokinetic disorder: it is most common and appears when levodopa blood concentration reaches its peak (1-2 hours after taking the drug), manifesting as involuntary movements of the hands, feet, trunk and tongue, unstable gait, and difficulties in speaking, eating and dressing. Peak dose isokinetic disorder is often a sign of high drug dose.
Treatment.
(1) Reduce the dose of compounded levodopa per dose.
(2) If the patient is on compounded levodopa alone, the dose may be reduced appropriately with the addition of a DR agonist or with the addition of a COMT inhibitor.
(3) Addition of amantadine.
(4) Replacement of compounded levodopa extended-release tablets with standard tablets. It has also been reported that a small amount of clozapine can control agent-peak isokinetic disorder.
2. Biphasic isokinetic disorder: patients with isokinetic disorder at the beginning and at the end of the drug onset are called biphasic isokinetic disorder, which manifests as Parkinson’s disease symptom remission-isokinetic disorder-remission-isokinetic disorder-Parkinson’s disease symptom, usually affecting the lower extremities, and may be related to the decreased storage capacity of dopamine and unstable blood concentration. Biphasic isokinetic disorder is more difficult to control, and a long half-life DR agonist or COMT inhibitor may be added, or a micro-pump continuous infusion of levodopa methyl, ethyl or DR agonist.
3. Dystonia: It appears when the efficacy of levodopa wears off and is dominated by painful spasm of calf gastrocnemius and toe, which is related to low blood concentration of levodopa. For dystonia appearing at night, levodopa controlled release or DR agonist can be added at bedtime; for early morning dystonia (also called morning stiffness or early morning motor inability), a dose of compounded levodopa standard tablets or water soluble tablets can be taken immediately after waking up. In severe cases, local injection of Botox is better for relieving local painful spasm.
Second, the symptoms fluctuate
It occurs between doses (mostly 3.5 hours after the previous dose) and is characterized by end-of-dose worsening and reappearance of Parkinson’s disease symptoms, and many patients also experience off-phase odd-motion disorder, such as painful foot spasms. Symptom fluctuations are common in patients who are effectively treated with levodopa, with the “end-of-dose phenomenon” appearing earlier and earlier as the duration of treatment increases. This phenomenon is often related to insufficient doses of levodopa and is predictable. It can be avoided in most patients by adopting a low-protein diet and increasing the dosage of levodopa and dividing it into multiple small doses.
On-Off” phenomenon
Some patients experience symptom fluctuations in the later stages of levodopa administration, with sudden and unpredictable changes between “on” and “off” states, sudden inactivity and sudden freedom of movement, independent of the duration of levodopa administration. The rate of change can be very rapid and unpredictable. Patients describe the changes as being like a power supply going on and off, so this phenomenon is clinically referred to as the “on/off” phenomenon.
The “on-off” phenomenon is most often seen in younger patients and occurs between 8 months and 1.5 years after the drug is administered. For the treatment of the “on-off” phenomenon, it is not recommended to increase the dose of levodopa, but to reduce the dose and increase the number of doses; or to use dopamine agonists, propargyl amphetamine to improve the symptoms; or thalamic nucleus electrical stimulation therapy.
IV. Freezing phenomenon
Patients usually take the medication on time and according to the dose, but will suddenly freeze, completely unable to move, and then relieved after a few minutes, this kind of performance similar to the “on-off” phenomenon is called the freezing phenomenon. The freezing phenomenon is not significantly related to the dose of levodopa applied, but is usually seen in patients with advanced long-term levodopa application and may be related to dopamine receptor sensitivity. Treatment can be tried with dopamine receptor agonists or through non-pharmacological treatments, such as sensory or cueing. Emotional tension can lead to the appearance of gait freezing, so relieving anxiety and tension can play a role.
Prevention of motor complications: The occurrence of motor complications is not only related to the long-term application of levodopa preparations, but also closely related to the total amount of medication used, age of onset, and duration of the disease. The greater the total amount of medication, the longer the duration of medication, the younger the age of onset, and the longer the duration of disease, the more likely it is that motor complications will occur. Both age of onset and duration of disease are uncontrollable factors, so the development of motor complications can be delayed as much as possible by optimizing the levodopa treatment regimen. It is important to emphasize that treatment must be individualized and that levodopa preparations should not be deliberately reduced or not used simply to delay the onset of motor complications.