Treatment principles
1. Comprehensive treatment.
Drug therapy is the most important treatment for Parkinson’s disease. Levodopa preparations are still the most effective drugs. Surgery is an effective supplement to pharmacotherapy. Rehabilitation therapy, psychotherapy and good care can also improve the symptoms to some extent. The currently applied treatments mainly improve the symptoms, but cannot stop the progress of the disease yet.
2. Medication principles.
It is advisable to gradually increase the dosage of drugs from small doses. To achieve a more satisfactory effect with a smaller dose, not to seek full effect. While following the general principles of medication, individualization should also be emphasized. According to the patient’s condition, age, occupation and economic conditions and other factors to adopt the best treatment plan. The medication should not only control the symptoms but also avoid the occurrence of side effects, and try to control the clinical symptoms for a long time from a long-term perspective.
Drug treatment
1. Protective therapy.
In principle, Parkinson’s disease should be given protective treatment as soon as it is diagnosed. At present, the main clinical drugs used as protective therapy are monoamine oxidase type B (MAO-B) inhibitors. Recent studies have shown that MAO-B inhibitors have the potential to slow down the progression of the disease, but there is no conclusive evidence yet.
2. Symptomatic treatment.
Early treatment (Hoehn-Yahr class l~II)
(1) When to start medication: When the disease is mild in the early stage and has no obvious effect on daily life or work, medication can be withheld. If the disease affects the patient’s daily life or ability to work, or if the patient requires early control of symptoms, then symptomatic treatment should be started.
(2) Preferred drug principles: Patients <65 years old and without mental retardation may choose.
(1) non-ergot dopamine receptor (dr) agonists;
②mao-b inhibitors;
③Amantadine, if tremor is obvious and other anti-pd drugs are not effective, then anticholinergic drugs can be used;
④Compound levodopa + catechol-oxo-methyltransferase (comt) inhibitors;
⑤ compound levodopa; ④ and ⑤ are generally added when ①, ② and ③ regimens are not effective. However, ④ or ⑤ may be preferred if the work requires significant improvement of motor symptoms or if cognitive impairment occurs, or ①, ② or ③ may be used in small doses in combination with ⑤. Patients ≥65 years of age or with mental retardation: compound levodopa is preferred, with the addition of dr agonists, mao-b or comt inhibitors if necessary. Benzedrine has a high number of side effects and should not be used if possible, especially in elderly male patients, except in cases of severe tremor and poor efficacy with other drugs.
Intermediate treatment (Hoehn-Yahr class III)
Patients who are treated with DR agonists, MAO-B inhibitors or amantadine/anticholinergic drugs in the early stage should be treated with the addition of levodopa if the original drugs are not effective in controlling symptoms; patients who are treated with low-dose levodopa in the early stage should be treated with an appropriate dose increase or addition of DR agonists, MAO-B inhibitors, amantadine, or anti-cholinergic drugs if the symptoms are not well controlled in the middle stage. -B inhibitors, amantadine or COMT inhibitors.
Late stage treatment (Hoehn-Yahr class IV-V)
Treatment of patients with advanced disease is relatively complex and difficult due to the progression of the disease itself and the emergence of motor complications. Therefore, a reasonable treatment plan should be formulated at the beginning of treatment, taking into account the actual situation of the patient, in order to delay the emergence of motor complications as much as possible and to extend the time window for effective treatment.
Commonly used therapeutic drugs
1. Anticholinergic drugs.
Mainly by inhibiting the activity of acetylcholine in the brain, correspondingly increasing the dopamine effect. Commonly used clinically is benzhexol hydrochloride. In addition, there are Kaimajun, benztropine, scopolamine, etc. It is mainly indicated for patients with significant tremor and younger age. It is used with caution in elderly patients and is contraindicated in patients with narrow-angle glaucoma and prostatic hypertrophy.
2. Amantadine.
It can promote the synthesis and release of dopamine in nerve endings and prevent its reabsorption. Mildly improve the effect of hypokinesis, rigidity, tremor, and may be effective for heterokinesis. Use with caution in patients with renal insufficiency, epilepsy, severe gastric ulcer and liver disease.
3. Monoamine oxidase B (MAO-B) inhibitors.
By irreversibly inhibiting MAO-B in the brain, it blocks the degradation of dopamine and relatively increases dopamine levels for therapeutic purposes. MAO-B inhibitors can be used as monotherapy for new-onset, young patients with Parkinson’s disease or as an adjunct to compound levodopa for patients with intermediate to advanced disease. It may have neuroprotective effects, so early use is recommended in principle. MAO-B inhibitors include sellegran and resagiline. Their use at night may cause insomnia, so early and mid morning use is recommended. Use with caution in patients with gastric ulcers and in combination with 5-hydroxytryptamine reuptake inhibitors (SSRI) is prohibited.
4. DR agonist.
Can directly stimulate dopamine receptors and play a role. Currently, the commonly used clinical non-ergot DR agonists. It is suitable for patients with early Parkinson’s disease, and can also be used in combination with compound levodopa for the treatment of patients in the middle and late stages. MAO-B inhibitors or DR agonists are preferred in young patients at the beginning of the disease course. All agonists should be started in small doses and gradually increased. The incidence of symptom fluctuations and allodynia is low with agonists, but the incidence of postural hypotension and psychiatric symptoms is high. Common side effects include gastrointestinal symptoms, drowsiness, and hallucinations. Non-ergot DR agonists include pramipexole, ropinirole, piribedil, rotigotine and apomorphine.
5. Compound levodopa (including levodopa/benserazide and levodopa/carbidopa).
Levodopa is a precursor of dopamine. Peripherally supplemented levodopa can cross the blood-brain barrier and be converted to dopamine by decarboxylation of dopa decarboxylase in the brain, thus exerting a substitution therapy effect. Benserazide and carbidopa are peripheral decarboxylase inhibitors that reduce the decarboxylation of levodopa in the periphery and increase the amount of levodopa entering the brain as well as reduce its peripheral side effects.
The dose should be increased gradually and slowly from a small dose until a more satisfactory effect is obtained, without seeking full effect. The dose should not be increased too quickly and the dosage should not be too large. Take the drug one hour before or one and a half hours after meals. Older patients can be used as early as possible, and monoamine oxidase B inhibitors or dopamine agonists should be preferred, especially in young patients with Parkinson’s disease, and compound levodopa should be considered when the above drugs cannot control symptoms well. It should be used with caution in patients with active peptic ulcers, narrow-angle glaucoma, and psychiatric patients.
6. Catechol-oxygen-position-methyltransferase (COMT) inhibitors.
Increases the amount of levodopa in the brain by reducing the metabolism of levodopa in the periphery through inhibition of COMT enzyme.COMT inhibitors include entacapone and tolcapone. COMT inhibitors can be added to Parkinson’s disease patients with fluctuating symptoms to reduce “off periods”. Entacapone needs to be taken at the same time as levodopa to be effective. Side effects of COMT inhibitors include diarrhea, headache, excessive sweating, dry mouth, elevated aminotransferase, abdominal pain, and yellowing of the urine. Tolcapone may cause liver function damage, and liver function should be closely monitored, especially during the first 3 months of use.
Prevention and treatment of complications
1. Diagnosis and treatment of motor complications.
Patients with mid- to late-stage Parkinson’s disease may develop motor complications, including symptom fluctuations and isokinetic disorders. Symptom fluctuation (motor fluctuation) includes wearing-off and on-off phenomenon. Wearing-off refers to the shortening of the effective duration of action of each dose. The typical complaint of patients at this time is “the medication does not work as well as it used to, it used to last 4 hours for one dose, but now it is over in 2 hours.” This can be done by increasing the number of daily doses or the dose per dose, or by switching to extended-release agents, or by adding other complementary medications. The “on-off” phenomenon is characterized by a sudden inability to move and a sudden freedom of movement, alternating between a few minutes and a few minutes. It is usually seen in severe cases and the mechanism is unknown. The typical complaint of patients at this time is “I used to be able to estimate when the drug would wear off after each dose, but now I can’t. The effect of the drug just disappears, very suddenly. Even when I think the effect of the medicine should still be there, it will suddenly wear off. Once the “on – off” phenomenon occurs, it is more difficult to deal with. Continuous infusion of levodopa methyl, ethyl, or DR agonists can be administered by micropump.
Dyskinesia, also known as dyskinesia, is characterized by involuntary choreiform or dystonic movements of the head, face, extremities, or trunk. It is called peak-dose dyskinesia when it occurs at the peak of levodopa blood concentration. The typical complaint of patients at this time is: “Every time the strength of the drug comes up, the body is not as hard, the movement is faster, and the shaking is lighter, but the body will shake involuntarily and cannot be controlled.”
The presence of biphasic dyskinesia at both the peak and end of the dose is called biphasic dyskinesia. The typical complaint of the patient in this case is: “Involuntary shaking of the body occurs every time the drug takes effect and is about to expire.” Painful muscle spasms of the foot or lower leg, called dystonia, occur early in the morning before the medication is taken and are also a manifestation of dystonia. A typical complaint of patients at this time is, “Often when I get up in the morning, I feel my foot gouging the ground, I can’t relax, and sometimes I feel pain.” Dose peak heterokinesia can be treated by reducing each levodopa dose, or by adding a DR agonist or amantadine. Biphasic dyskinesia is more difficult to control and can be treated with the addition of a long half-life DR agonist or COMT inhibitor, or a continuous infusion of levodopa methyl, ethyl, or DR agonist by micropump. Dystonia can be increased or decreased accordingly to the corresponding levodopa preparation dose depending on whether it occurs at the end of the dose or at the peak of the dose.
2. 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, age of onset, and duration of 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 regimen. In patients with new onset, MAO-B inhibitors or DR agonists are preferred to delay the application of levodopa; levodopa should be started in small doses and gradually increased; symptom control can meet the needs of daily life without full effect; all of these can delay the emergence of motor complications to some extent. However, it should be emphasized that treatment must be individualized, and levodopa preparations should not be deliberately reduced or not used simply to delay the emergence of motor complications.
Treatment of non-motor symptoms
1. Treatment of mental disorders.
Patients with Parkinson’s disease can develop psychiatric symptoms such as hallucinations, euphoria, and delusions in the late stage of the disease. The anti-PD drugs can also cause psychiatric symptoms, the most common ones being benzhexol hydrochloride and amantadine. Therefore, when patients develop psychiatric symptoms, first consider gradually reducing or discontinuing anticholinergic drugs, amantadine, selagiline, DR agonists, and compound levodopa in order. For those who are ineffective in medication adjustment or cannot stop anti-PD drugs due to heavy symptoms, antipsychotic drugs such as clozapine and quetiapine can be added. PD patients with cognitive impairment can be added with cholinesterase inhibitors, such as staphylococcus aureus, donepezil, and carboplatin.
2. Treatment of autonomic dysfunction.
Patients with constipation can increase water intake and eat more fiber-rich foods. Also reduce the dose of anticholinergic drugs or take laxative drugs. Patients with urinary disorders may reduce water intake after dinner and may also try peripheral anticholinergics such as oxybutynin and scopolamine. Patients with postural hypotension should increase salt and water intake, may wear elastic stockings, or may add the alpha-adrenergic agonist Midodrine.
3. Sleep disorders.
Patients with Parkinson’s disease may have sleep disorders such as difficulty falling asleep, excessive dreaming, easy waking, and early awakening. If the sleep disorder in PD is due to exacerbation of the disease at night, levodopa controlled-release agent can be added at night before bedtime. If the patient has restless legs syndrome affecting sleep at night DR agonist can be added at bedtime. Sedative sleeping agents may be used if sleep is not improved despite adjustment of anti-PD medications. [3]
Surgical treatment
There are two main surgical approaches, neurodesis and deep brain electrical stimulation (DBS). The common targets for nucleus disruption are the ventral intermediate nucleus of the thalamus (Vim) and the posterior ventral part of the pallidum (PVP). The thalamic ventral intermediate nucleus (VIM) is most often chosen for patients with predominant tremor, and the posterior ventral part of the pallidum is most often chosen as a target for patients with predominant rigidity. Nucleus disruption is still used in some places because of its low cost and also its efficacy. Deep brain electrical stimulation has been used as the surgical treatment of choice because it is minimally invasive, safe, and effective. Patients with Parkinson’s disease who present with markedly diminished efficacy or allodynia and whose symptoms are not well improved by pharmacological adjustments may be considered for surgical treatment. Surgery is more effective for limb tremor and myotonia, while there is no significant improvement in the function of mid-axis symptoms such as postural gait abnormalities and swallowing difficulties. Surgery, like medication, can only improve symptoms, but not cure the disease or stop its progression. Medication is still required after surgery, but the dose can be reduced. Surgery is not effective in patients with secondary Parkinson’s syndrome and Parkinson’s superimposed syndrome. Patients with early-stage Parkinson’s disease who are well treated with medications are not candidates for premature surgery.