[Treatment Principles
I. Comprehensive treatment
A comprehensive and integrated treatment should be adopted for motor and non-motor symptoms of Parkinson’s disease. Treatment methods and means include medication, surgery, exercise therapy, psychological guidance and care. Drug therapy is preferred and is the main treatment throughout the treatment process, while surgery is an effective complement to drug therapy. The currently applied treatments, whether pharmacological or surgical, can only improve the patient’s symptoms, but cannot stop the development of the disease, let alone cure it. Therefore, treatment should not only be based on the present, but also requires long-term management to achieve long-term benefits.
Second, the principle of medication
The principle of medication should be aimed at achieving effective improvement of symptoms, work ability and quality of life. Early diagnosis and early treatment can not only improve the symptoms but also slow down the disease progression. Dose titration” should be adhered to in order to avoid acute side effects of drugs and to achieve the principle of “achieving satisfactory clinical effects with as small a dose as possible”, so as to avoid or reduce the incidence of motor complications, especially ochronosis.
Treatment should follow the evidence of evidence-based medicine, and should also emphasize the characteristics of individualization. The selection of medication for different patients should take into account the characteristics of the patient’s disease (whether it is predominantly tremor or tonic hypokinesia) and the severity of the disease, the presence of cognitive impairment, age of onset, employment status, the presence of co-morbidities, possible side effects of medication, the patient’s willingness, affordability and other factors, in order to avoid, delay or reduce as much as possible side effects and motor complications of medications. When performing anti-Parkinson’s disease drug therapy, especially when using levodopa, the drug should not be stopped suddenly to avoid withdrawal malignant syndrome.
Drug therapy]
According to the severity of clinical symptoms, the course of Parkinson’s disease can be divided into early and intermediate and late stages, i.e. Hoehn-Yahr grade l-2.5 is defined as early stage, and Hoehn-Yahr grade 3-5 is defined as intermediate and late stage. Below we present specific treatment advice for early and mid to late stage Parkinson’s disease, respectively.
I. Treatment of early Parkinson’s disease
Once early diagnosis is made, treatment should be started as early as possible to grasp the timing of disease modification, which plays a key role in the success or failure of the entire treatment of Parkinson’s disease in the future. Early treatment can be divided into non-pharmacological treatment (including awareness and understanding of the disease, supplemental nutrition, strengthening exercise, firm confidence in overcoming the disease, as well as social and family understanding, care and support for patients) and pharmacological treatment. Generally, monotherapy is given in the early stage of the disease, but the combination of multiple drugs (embodying multiple targets) in optimized small doses can also be used to achieve the goal of optimal efficacy, longer maintenance time and lowest incidence of exercise complications.
Pharmacological treatments include disease-modifying therapeutic agents and symptomatic therapeutic agents. In addition to their potential disease-modifying effects, disease-modifying drugs also have a symptom-modifying effect; symptomatic drugs, in addition to significantly improving disease symptoms, also have some disease-modifying effects.
The goal of disease-modifying therapy is to delay the progression of the disease. Currently, the main clinical drugs that may have disease-modifying effects include monoamine oxidase type B (MAO-B) inhibitors and dopamine receptor (DR) agonists, etc. Among the MAO-B inhibitors, selagiline + vitamin E (DATATOP) and resagiline (ADAGIO) may have the effect of delaying disease progression in clinical trials; among the DR agonists, pramipexole CALM- PD study and the ropinirole REAL-PET study suggest a possible disease-modifying effect. Clinical trials of coenzyme Q10 at high doses (1200 mg/d) also suggest a possible disease-modifying effect.
(A) Preferred drug principles
1, early-onset patients, in the absence of concomitant hypo-intelligence, may have the following options.
①Non-ergot DR agonists;
②MAO-B inhibitors;
③Amantadine;
④Compound levodopa;
⑤ compound levodopa + catechol-0-methyltransferase (COMT) inhibitors. The preferred drugs are not in the above order, and different regimens should be chosen according to the specific conditions of each patient. If the patient cannot afford the high price of the drug for financial reasons, then regimen ③ may be preferred; if the patient needs to work for special reasons, to improve motor symptoms significantly, or to have cognitive impairment, then regimen ④ or ⑤ may be preferred; also, regimen ④ may be used in combination with a low dose of regimen ①, ② or ③. In cases where tremor is obvious and other anti-Parkinsonian drugs are ineffective, anticholinergic drugs, such as benzodiazepines, can be used.
2. In patients with late onset disease or with concomitant hypo-intelligence, compound levodopa therapy is generally preferred. As symptoms worsen, DR agonists, MAO-B inhibitors or COMT inhibitors can be added to the treatment when the efficacy decreases. Try not to apply anticholinergic drugs, especially for elderly male patients, because they have more side effects.
(B) Therapeutic drugs
1.Anticholinergic drugs: At present, benzhexol is mainly applied in China at a dose of 1-2 mg, 3 times/d. It is mainly applied to patients with tremor, while it is not recommended for patients without tremor. For patients <60 years old, it is important to inform that long-term application of this class of drugs may cause their cognitive function to decline, so the cognitive function should be reviewed regularly and discontinued as soon as the patient's cognitive function is found to decline; for patients ≥60 years old, it is best not to apply anticholinergic drugs. Narrow-angle glaucoma and prostatic hypertrophy patients are prohibited.
2, amantadine: the dose is 50-100mg, 2-3 times / d, the last time should be taken before 4 pm. It has an ameliorative effect on hypokinesia, tonicity, tremor and is helpful in improving heterokinesia (Class C evidence). Use with caution in patients with renal insufficiency, epilepsy, severe gastric ulcer, liver disease, and contraindicated in lactating women.
3.Compound levodopa (benserazide levodopa, carbidopa levodopa): the initial dosage is 62.5~125.0 mg, 2~3 times/d, gradually increase the dosage to the appropriate dose for maintenance with satisfactory efficacy and no side effects according to the condition, and take the drug l h before or 1.5 h after meal. Previously, it was advocated to postpone the application as much as possible because the early application induced xerostomia; available evidence suggests that the early application of small doses (≤400 mg/d) does not increase the occurrence of xerostomia. The rapid onset of action of compounded levodopa in regular release and the relatively long maintenance time of controlled release, but the slow onset of action and low bioavailability, require attention when using, especially when switching between the 2 different dosage forms. Active peptic ulcers, narrow-angle glaucoma, psychiatric patients are prohibited.
4, DR agonists: most of the current push for non-ergot DR agonists as the drug of choice, especially for early-onset Parkinson’s disease patients in the early stages of the disease. Because, these long half-life agents can avoid the DR of the striatal postsynaptic membrane “pulse” like stimulation, thus preventing or reducing the occurrence of motor complications. The side effects of DR agonists are similar to those of compounded levodopa, except that they have a low incidence of symptom fluctuations and allodynia, and a higher incidence of postural hypotension, ankle edema, and psychiatric abnormalities (hallucinations, hyperphagia, hypersexuality, etc.).
There are 2 types of DR agonists, the ergot class including bromocriptine, pergolide, d-dihydroergotocriptine, ergometrine, and ergometrine; and the non-ergot class including pramipexole, ropinirole, piribedil, rotigotine, and apomorphine. Ergot DR agonists can lead to heart valve lesions and pulmonary pleural fibrosis, therefore, their use is no longer advocated, of which Pergolide has been discontinued in China.
Non-ergot DR agonists that have been on the market for many years in China are.
①Piberidil extended-release: the initial dose is 50 mg once daily, which can be changed to 25 mg twice daily for patients prone to side effects, and increased to 50 mg twice daily in the second week, with an effective dose of 150 mg/d, divided into 3 oral doses, with the maximum dose not exceeding 250 mg/d;
②Praxol: there are 2 dosage forms: normal release and extended release. The usage of normal release: the initial dose is 0.125 mg 3 times a day (1 or 2 times for individual patients prone to side effects), increasing by 0.125 mg 3 times a day every week, and the general effective dose is 0.50-0.75 mg 3 times a day, with the maximum dose not exceeding 4.5 mg/d. The usage of extended release: the daily dose is the same as normal release, but is taken once a day.
Upcoming non-ergot DR agonists are: ① Ropinirole: initial dose of 0.25 mg, 3 times daily, increasing by 0. 75 mg per week to 3 mg per day, the general effective dose is 3 to 9 mg per day, divided into 3 doses, the maximum daily dose is 24 mg; ② Rotigotine: initial dose of 2 mg, once daily, increasing by 2 mg per week, the general effective dose is 6 to 8 mg per day for early stage patients, and 6 to 8 mg per day for intermediate to late stage patients. The effective dose is generally 6 to 8 mg daily for early stage patients and 8 to 16 mg for patients in the middle and late stages.
Ergot DR agonists that have been marketed in China for many years are.
①Bromocriptine: 0. 625 mg once daily, increasing by 0. 625 mg every 5 days, effective dose 3.75-15. 00 mg/d, divided into 3 oral doses;
②a-dihydroergotocryptine: 2.5 mg twice daily, increased by 2.5 mg every 5 days, effective dose 30～50 mg/d in 3 oral doses. The dose conversion between the above 5 drugs is: piribedil: pramipexole: ropinirole: bromocriptine: d-dihydroergotocryptine = 100:1:5:10:60), due to individual differences only as a reference.
5, MAO-B inhibitors: mainly sellegran and resagiline, of which sellegran is available as normal release and oral mucosal disintegrating agent. The usage of Silegiline (normal release) is 2.5-5.0 mg twice daily, taken in the morning and noon, not in the evening or at night to avoid insomnia, or combined with vitamin E 2000 U (DATATOP program); oral mucosal disintegration agent absorption, action, safety are better than Silegiline normal release, the dosage is 1. 25-2.50 mg/d. Raisagiline’s The dosage is 1 mg once a day, taken in the morning. Gastric ulcer patients are cautiously used, and the combination with 5-hydroxytryptamine reuptake inhibitors (SSRI) is prohibited.
6, COMT inhibitors: In the early stage of the disease, compound levodopa + COMT inhibitors such as entacapone bidopa tablets (a combination of entacapone/levodopa/carbidopa, divided into four dosage forms according to the dose of levodopa, can not only improve the patient’s symptoms, but also may prevent or delay the occurrence of motor complications, but FIRST-STEP and STRIDE-PD However, FIRST-STEP and STRIDE-PD studies suggest that the early application of entacapone bidopa does not delay motor complications and increases the chance of atopic disorder, which is still controversial and needs to be further verified.
The dosage of entocapone is 100-200 mg per dose, and the number of doses is the same as that of levodopa, or less than that of levodopa if the number of daily doses is higher. Side effects include diarrhea, headache, excessive sweating, dry mouth, elevated transaminases, abdominal pain, and yellowing of urine. Tolcapone may cause liver damage and liver function needs to be monitored closely, especially during the first 3 months after the drug is administered.
II. Treatment of mid- to late-stage Parkinson’s disease
The clinical manifestations of mid- to late-stage Parkinson’s disease, especially advanced Parkinson’s disease, are extremely complex, with the progression of the disease itself, as well as the involvement of drug side effects or motor complications. The treatment of patients with mid- to late-stage Parkinson’s disease should, on the one hand, continue to strive to improve the patients’ motor symptoms; on the other hand, some motor complications and non-motor symptoms should be properly managed.
(A) Treatment of motor complications
Motor complications (symptom fluctuations and dyskinesia) are common symptoms in the middle and late stages of Parkinson’s disease. Adjusting the type, dose and number of medications can improve symptoms, and surgical treatment such as deep brain electrical stimulation (DBS) is also effective.
1. Treatment of symptom fluctuations: Symptom fluctuations mainly include end-dose deterioration and on/off phenomenon.
The treatment of end-of-dose worsening is as follows
(1) Do not increase the total daily dose of compounded levodopa, but increase the number of doses per day and reduce the dose per dose (provided that it is still effective in improving motor symptoms), or increase the total daily dose (if the original dose is not large), and increase the number of doses per dose;
② Switching from regular release to controlled release to prolong the duration of action of levodopa is more appropriate for early onset of end-of-dose deterioration, especially at night, and the dose should be increased by 20%-30% (US guidelines consider that it cannot shorten the “off” period, which is level C evidence, while UK NICE guidelines recommend it for use in patients with advanced disease, but not as a first choice, as level B evidence);
③Add DR agonists with long half-life, including pramipexole and ropinirole as level B evidence, carte blanche and apomorphine as level C evidence, bromocriptine cannot shorten the “off” period, as level C evidence, if the DR agonist has been used and the efficacy is reduced, try to switch to another DR agonist;
④Add a COMT inhibitor that produces sustained DAergic stimulation of the striatum, of which entocapone is level A evidence and tolcapone is level B evidence;
⑤ Add MAO-B inhibitors, of which resagiline is level A evidence and sellegrin is level C evidence;
⑥Avoid the effect of diet (containing protein) on the absorption of levodopa and its passage through the blood-brain barrier; it is advisable to take the drug 1h before or 1.5h after meals; adjustment of protein diet may be effective;
(7) Surgical treatment mainly for the thalamic floor nucleus (STN) may be beneficial with DBS, which is level C evidence. The management of the on-off phenomenon is more difficult, oral DR agonists can be used, or micro-pump continuous infusion of levodopa methyl or ethyl ester or DR agonists (such as ergocalciferol, etc.) can be used.
2, the treatment of isokinetic disorders: isokinetic disorders (AIMs), also known as movement disorders, including agent peak isokinetic disorder, biphasic isokinetic disorder and dystonia.
The treatment of agent peak isokinetic disorder is.
(i) Reduce the dose of compounded levodopa for each dose;
②If the patient is using compound levodopa alone, the dose can be reduced appropriately and DR agonist can be added at the same time or COMT inhibitor can be added;
③Add amantadine (level C evidence);
④Add atypical antipsychotics such as clozapine;
⑤ If a compounded levodopa controlled-release agent is used, it should be replaced with a regular-release agent to avoid the cumulative effect of the controlled-release agent.
The treatment of biphasic heteronegativity (including early and late dose heteronegativity) is as follows.
①If compounded levodopa controlled-release agent is used, it should be replaced with normal-release agent, preferably with water solvent, which can effectively alleviate the first-dose anomaly;
②Adding a DR agonist with a long half-life or a COMT inhibitor with an extended levodopa plasma clearance half-life can alleviate end-dose anisotropy and may also help to improve first-dose anisotropy. Continuous infusion of DR agonists or levodopa methyl or ethyl ester by micropump can improve both isokinetic disorder and symptom fluctuations, and oral formulations are being tested to see if the same effect can be achieved.
Clinical trials related to the therapeutic efficacy of other drugs for the treatment of athetoid disorder such as adenosine A2A receptor antagonists acting on non-DAergic aspects of the basal ganglia are underway. The management of morning dystonia is based on the addition of a combination of levodopa controlled-release tablets or a long-acting DR agonist at bedtime, or a combination of levodopa regular-release or aqueous solution before waking up; the management of “open” dystonia is based on the same dose of peak anisokinesia. Surgical treatment is mainly DBS, which can be beneficial.
(B) Treatment of postural balance disorder
Postural balance disorder is the most common cause of falls in patients with Parkinson’s disease, and it occurs easily when changing positions such as turning, rising and bending. Active body weight adjustment, stepping, striding, listening to commands, walking to music or clapping, or crossing objects (real or imaginary) may be beneficial. Use a walker or even a wheelchair if necessary and be well protected.
(iii) Treatment of non-motor symptoms
The non-motor symptoms of Parkinson’s disease involve many types, including sensory disorders, mental disorders, autonomic dysfunction and sleep disorders, and require active and appropriate treatment.
Treatment of psychiatric disorders: The most common psychiatric disorders include depression and/or anxiety, hallucinations, cognitive impairment or dementia. The first step is to identify whether the psychiatric disorder is induced by anti-Parkinsonian drugs or caused by the disease itself. If the former is the case, the following anti-Parkinsonian drugs need to be reduced or discontinued sequentially according to the odds of easily induced mental disorders: anticholinergics, amantadine, MAO-B inhibitors, DR agonists; if the patient’s symptoms still exist after taking the above measures, the compound levodopa can be gradually reduced on the premise that it does not significantly aggravate the motor symptoms of Parkinson’s disease. If the effect of medication adjustment is not satisfactory, it suggests that the patient’s mental disorder may be caused by the disease itself, and symptomatic medication should be considered.
For treatment of hallucinations and delusions, clozapine or quetiapine is recommended, the former being slightly more effective than the latter, but clozapine has a 1 to 2 percent chance of causing granulocyte deficiency, so blood counts need to be monitored. For the treatment of depression and/or anxiety, selective SSRIs can be applied, as well as DR agonists, especially pramipexole, which can improve both motor symptoms and depressive symptoms. Lorazepam and diazepam are very effective in relieving irritable states. For the treatment of cognitive impairment and dementia, cholinesterase inhibitors such as rivastigmine and donepezil can be applied, as well as meperidine, of which rivastigmine is more well documented.
2, treatment of autonomic dysfunction: the most common autonomic dysfunction includes constipation, urinary disorders and positional hypotension. For constipation, intake of sufficient fluids, fruits, vegetables, fiber and lactulose (10-20g/d) or other mild laxative drugs can improve constipation symptoms, such as lactulose, dragon aloe pills, rhubarb tablets, senna, etc.; gastric motility drugs, such as domperidone and mosapride, can also be added. Anticholinergics need to be discontinued and exercise needs to be increased.
For the treatment of urinary frequency, urgency and urge incontinence in urinary disorders, peripheral anticholinergic drugs such as oxybutynin, bromopamine tylenol, tolterodine and scopolamine can be used; while cholinergic preparations are given to those with no reflexes in the forced urinary muscles (but they need to be used with caution because they can aggravate the motor symptoms of Parkinson’s disease). If urinary retention occurs, intermittent clean catheterization should be taken, and if caused by prostatic hyperplasia and hypertrophy, severe cases, if necessary Surgical treatment may be performed. Patients with positional hypotension should increase salt and water intake; sleep in an elevated head position, do not lie flat; can wear elastic pants; do not rise quickly from a recumbent or sitting position; preferred treatment with the alpha-adrenergic agonist Midodrine, and the best efficacy; can also use the selective peripheral dopamine receptor antagonist domperidone.
3, the treatment of sleep disorders: sleep disorders mainly include insomnia, rapid eye movement sleep behavior abnormalities (RBD), excessive daytime sleepiness (EDS). The most common problem with insomnia is difficulty maintaining sleep (also known as sleep fragmentation). Frequent awakenings may allow tremor to reappear during light sleep, or the patient may have difficulty turning over at night due to inability to move at night because the concentration of dopaminergic drugs taken during the day has been depleted during the night, or increased nocturnal urination. If associated with nocturnal symptoms of Parkinson’s disease, the addition of a levodopa controller, DR agonist, or COMT inhibitor may be effective.
If you are taking Slegiline or Amantadine, especially in the evening, you should first correct the time of day by taking Slegiline in the morning or at noon and Amantadine before 4:00 p.m. If there is no significant improvement, you should reduce or even stop the dose or use a short-acting sedative. EDS may be related to the severity of Parkinson’s disease and cognitive decline, and may also be related to the application of anti-Parkinson’s disease drugs DR agonists or levodopa. If the patient is drowsy after each dose, it suggests an overdose, and reducing the dose will help improve EDS; levodopa controlled-release agents can also be given instead of regular-release agents, which may help avoid or reduce post-dose drowsiness.
4, treatment of sensory disorders: the most common sensory disorders include hyposmia, pain or numbness, restless legs syndrome (RLS). Olfactory hyposmia is quite common in patients with Parkinson’s disease and occurs many years before the onset of motor symptoms, but there are no clear measures to improve olfactory impairment.
Pain or numbness is common in Parkinson’s disease, especially in patients with advanced Parkinson’s disease, and can be caused by the disease or by concomitant bone and joint pathology. If the pain or numbness decreases or disappears during the “open phase” of anti-Parkinson’s disease medication and returns during the “closed phase,” then it may be caused by Parkinson’s disease and treatment can be adjusted to prolong the “open phase. Conversely, other diseases or causes may be responsible and treatment may be chosen accordingly. For patients with Parkinson’s disease with RLS, DR agonists such as pramipexole within 2 h before going to sleep are very effective, or levodopa can be given as a compound.
Surgical treatment
Surgery can be considered in patients with significant early drug treatment, but with significantly reduced efficacy of long-term treatment, or with severe motor fluctuations and dyskinesia, as described in the Chinese Expert Consensus on Deep Brain Electrical Stimulation for Parkinson’s Disease. It is important to emphasize that surgery can significantly improve motor symptoms, but cannot cure the disease.
Patients with Parkinson’s superimposed syndrome in non-primary Parkinson’s disease are contraindications to surgery. Surgery has a good effect on limb tremor and/or myotonicity, but has no significant effect on somatic mid-axis symptoms such as postural balance disorders. Surgical approaches include nerve nucleus destruction and DBS, with DBS being the primary choice because of its relatively noninvasive, safe, and modifiable nature.
The surgical targets include the pale globus medialis (GPI), ventral intermediate nucleus (VIM) and thalamic nucleus (STN), with DBS in the STN being the most effective in improving tremor, bradykinesia, bradykinesia and anisokinesia. Preoperative levodopa sensitivity is an indicator of prognosis for STN DBS (level B evidence), age and duration of disease are indicators of prognosis for STN DBS, and young patients with a short duration of disease may improve more than older patients with a longer duration of disease (level C evidence), however, there is insufficient evidence to make any recommendations regarding prognostic factors for GPI and VIM DBS (level U evidence).
Rehabilitation and Exercise Therapy
Rehabilitation and exercise therapy may be helpful in improving the symptoms of Parkinson’s disease and even in slowing the progression of the disease. Patients with Parkinson’s disease often have gait disorders, postural balance disorders, speech and/or swallowing disorders, etc. Rehabilitation or exercise training can be performed according to the different mobility disorders. Exercises such as aerobics, tai chi, jogging, etc.; speech disorder training, gait training, postural balance training, etc. can be performed. If adhered to daily, it will help to improve the patient’s self-care ability, improve motor function, and prolong the validity of medication.
Psychological guidance
Patients with Parkinson’s disease mostly have depression and other psychological disorders. Depression can occur before and after the appearance of motor symptoms in Parkinson’s disease, and is one of the main risk factors affecting patients’ quality of life, as well as affecting the effectiveness of anti-Parkinson’s disease drug therapy. Therefore, the treatment of Parkinson’s disease should not only focus on improving patients’ motor symptoms, but also pay attention to improving patients’ depression and other psychological disorders, and give equal importance to effective psychological guidance and antidepressant medication, so as to achieve more satisfactory treatment results.
Caring care
In addition to professional drug treatment, scientific care is also important to maintain the quality of life of patients with Parkinson’s disease. Scientific care is often an adjunct to effective control of the disease and improvement of symptoms; it can also effectively prevent possible accidents such as accidental aspiration or falls.
In conclusion, there is no absolute fixed pattern for the treatment of Parkinson’s disease, as there may be differences in symptoms and sensitivity to treatment among different patients. The need for treatment varies from patient to patient, and the same patient’s need for treatment varies at different stages of the disease. Therefore, this guideline may apply to the general rule, but in clinical practice, care should be taken to understand in detail the patient’s condition (severity of disease, type of symptoms, etc.), response to treatment (whether it is effective, duration of onset of action, duration of maintenance of action, prolongation of the “on” period and “off” period When applying the drug, we should pay attention to the patient’s condition (severity of disease, type of symptoms, etc.), treatment response (whether it is effective, onset of action, duration of maintenance of action, prolongation of “on” and “off” period, and whether there are side effects or complications), and combine with your own treatment experience to follow the guidelines and reflect the principle of individualization in order to achieve more ideal treatment results.