What are the treatments for Parkinson's disease?

Parkinson's disease (PD) is a common degenerative disease of the nervous system in middle-aged and elderly people. The clinical manifestations of motor symptoms such as tremor, muscle rigidity, bradykinesia, and postural balance disorders and non-motor symptoms such as sleep disorders, olfactory disorders, autonomic dysfunction, cognitive and mental disorders are prominent features. The prevalence rate in people over 65 years old in my country is 1.7%. As the disease progresses, the motor and non-motor symptoms of PD will gradually worsen, which will not only impair the patient's daily activities, but also bring huge social and medical burdens.

* Treatment principles for PD

1. Comprehensive treatment

Every PD patient may have motor symptoms and non-motor symptoms successively or simultaneously, but both types of symptoms will occur throughout the course of the disease, and sometimes multiple non-motor symptoms will occur. Not only will motor symptoms affect the patient's ability to work and daily life, but non-motor symptoms will also significantly interfere with the patient's quality of life. Therefore, comprehensive and integrated treatment should be adopted for the motor symptoms and non-motor symptoms of PD.

2. Multidisciplinary Treatment Model

PD treatment methods and means include drug therapy, surgical treatment, botulinum toxin treatment, exercise therapy, psychological intervention, care and nursing, etc. Drug therapy is the first choice and the main treatment method in the entire treatment process. Surgery is an effective supplement when drug treatment is ineffective. Botulinum toxin injection is an effective method for treating local spasms and dystonia. Exercise and rehabilitation therapy, psychological intervention and care and nursing are applicable to the entire PD treatment process. When conditions permit, forming a multidisciplinary team can more effectively treat and manage PD patients and bring greater benefits to patients.

3. Full-process management

The current treatment methods, whether drugs or surgery, can only improve symptoms, but cannot prevent the progression of the disease, let alone cure it. Therefore, treatment is not only based on the present, but also requires long-term management to achieve long-term benefits.

*Medication

Principles of medication for PD

The motor and non-motor symptoms of the disease will affect the patient's ability to work and daily life. The principle of medication is to effectively improve symptoms, avoid or reduce adverse reactions, and improve work ability and quality of life.

Advocating early diagnosis and early treatment can not only better improve symptoms but also delay the progression of the disease.

Adhering to "dose titration" to avoid acute adverse drug reactions and striving to achieve the medication principle of "achieving satisfactory clinical effects with the smallest possible dose" can avoid or reduce the incidence of movement complications, especially dyskinesia.

Treatment should follow evidence-based medicine and should also emphasize individual characteristics. The choice of medication for different patients needs to comprehensively consider factors such as the patient's disease characteristics and disease severity, age of onset, employment status, cognitive impairment, comorbidities, possible adverse drug reactions, patient willingness, and economic affordability. Avoid, delay, or reduce adverse drug reactions and movement complications as much as possible.

Anti-PD drug treatment should not be stopped suddenly, especially when using levodopa and high-dose dopamine receptor agonists, so as to avoid withdrawal malignant syndrome.

2. Drug treatment of early PD

According to the severity of clinical symptoms, Hoehn-Yahr grading 1.0~2.5 is defined as early stage. Once the disease occurs, it will gradually worsen over time. There is evidence that the disease progresses faster in the early stage than in the later stage. Therefore, once the early diagnosis is made, early treatment should be started to grasp the opportunity of disease modification, which plays an important role in the long-term management of disease treatment.

Early treatment can be divided into non-drug treatment (including knowledge and understanding of the disease, nutritional supplements, strengthening exercise rehabilitation, firm confidence in overcoming the disease, and the understanding, care and support of the patient by society and family) and drug treatment. Generally, monotherapy is started, but two drugs with different mechanisms of action (targeting multiple targets) can also be used in combination at low doses, striving for the best efficacy, longer duration of maintenance, and lower incidence of acute adverse reactions and movement complications.

1. Disease-modifying therapy for early PD

The goal of disease-modifying treatment is to both slow the progression of the disease and improve the patient's symptoms.

Drugs that may have disease-modifying effects mainly include monoamine oxidase type B inhibitors (MAO-BI) and dopamine receptor agonists (DAs). Rasagiline and selegiline in MAO-BI may have disease-modifying effects; studies suggest that ropinirole in DAs may have disease-modifying effects.

2. Symptomatic treatment of early PD

There are currently a variety of drugs that can effectively improve PD. When choosing drugs, the patient should be the center, and the selection and adjustment should be based on the patient's age, symptoms, disease severity, comorbidities, work and living environment, etc.

1. Compound levodopa (dopasildazine, carbidopa): Levodopa is the standard treatment for PD and the most effective symptomatic drug for PD. As the disease progresses and long-term use of levodopa, motor complications will occur, including symptom fluctuations and dyskinesias.

Early use of low-dose levodopa (less than 400 mg/d) does not increase the occurrence of dyskinesia; compared with the treatment duration of levodopa, high-dose levodopa and long course of disease have a greater impact on the risk of dyskinesia.

Therefore, it is not recommended to deliberately delay the use of levodopa in the early stage, especially for patients with late-onset PD or younger patients with high demand for motor function improvement. Compound levodopa can be used as the first choice, but the effective dose should be maintained as low as possible while satisfying symptom control.

2. Dopamine receptor agonists: Non-ergot drugs are mainly recommended and are the first choice for early-onset patients in the early stages of the disease, including pramipexole, ropinirole, piribedil, rotigotine, and apomorphine. It should be noted that most dopamine receptor agonists have the risk of drowsiness and psychiatric adverse reactions, and the dose needs to be titrated gradually from a small dose.

In the early stages of the disease, levodopa and dopamine receptor agonists are used in combination at small doses to fully utilize the synergistic effects of the two drugs and delay dose-dependent adverse reactions. This is now very commonly used clinically. Early addition of DAs may delay the onset of dyskinesia.

3. MAO-BI: including the first-generation MAO-BI selegiline sustained-release tablets and orodisintegrating tablets and the second-generation MAO-BI rasagiline, as well as dual-channel blockers safinamide and zonisamide. It improves the motor symptoms of PD and is mainly recommended for the treatment of early PD patients, especially early-onset or first-time PD patients, and is also used as an add-on treatment for patients with advanced PD.

Rasagiline has more evidence than selegiline in improving motor complications. Do not use selegiline in the evening or at night to avoid insomnia.

4. Catechol-O-methyltransferase inhibitors (COMTI): Entacapone, tolcapone, opicapone, and entacapone bidopa tablets combined with compound levodopa (entacapone/levodopa/carbidopa compound preparation, divided into 4 dosage forms according to different levodopa doses). Entacapone bidopa tablets are the first choice for treatment in the early stage of the disease to improve symptoms, and adding COMTI treatment in the middle and late stages of the disease can further improve symptoms.

It should be pointed out that entacapone must be taken with compound levodopa and is ineffective when used alone. The first dose of tolcapone is taken with compound levodopa each day, and it can be used alone thereafter, generally every 6 hours, but liver function needs to be closely monitored.

5. Anticholinergics: Trihexyphenidyl is suitable for patients with tremors, but is not recommended for patients without tremors.

Patients under 60 years old should be informed that long-term use may lead to cognitive decline, so cognitive function should be screened regularly, and the drug should be discontinued if cognitive decline is found. Patients over 60 years old should not use the drug or use it as little as possible. If it must be used, the dosage should be controlled.

6. Amantadine: It improves hypokinesia, rigidity, and tremor, and is effective in improving dyskinesia.

*Recommendations:

(1) For early-onset PD without mental retardation, the following options are available: ① non-ergot DAs; ② MAO-BI; ③ compound levodopa; ④ entacapone bidopa tablets; ⑤ amantadine; ⑥ anticholinergic drugs. For patients with mental retardation, compound levodopa should be selected. The preferred drugs are not in the above order, and different options should be selected according to the specific conditions of different patients. If the European and American treatment guidelines are followed, option ① may also be preferred, or option ③ may be preferred; if special work requires significant improvement of motor symptoms, option ③ or ④ may be preferred; when using option ① or ② in small doses, option ③ may be used in combination with small doses; if drug economic factors are considered, option ⑤ may be preferred for patients with rigidity and hypokinetic type, and option ⑥ may also be preferred for patients with tremor type.

(2) Late-onset PD or early-onset patients with intellectual impairment: Compound levodopa is generally the first choice for treatment. DAs, MAO-BI or COMTI can be added as symptoms worsen and the efficacy decreases. Anticholinergic drugs should be avoided as much as possible, especially in elderly male patients, because they have more adverse reactions.

Figure 1 is a detailed flowchart for reference, which recommends how to choose medication based on clinical symptoms, different ages, and disease progression.

Figure 1: Parkinson's disease drug treatment process

3. Drug treatment of advanced PD

According to the severity of clinical symptoms, HY grade 3 to 5 is defined as mid-to-late stage PD. The clinical manifestations of late stage PD are extremely complex, including the progression of the disease itself, adverse drug reactions or motor complications. The treatment of patients with mid-to-late stage PD should not only continue to strive to improve motor symptoms, but also properly deal with some motor complications and non-motor symptoms.

1. Treatment of motor symptoms and postural balance disorders

When the disease enters the middle and late stages, motor symptoms worsen, slow movements become more serious, daily living ability is significantly reduced, and posture and balance disorders, freezing gait, and easy falls occur. To improve the above symptoms, it is necessary to increase the dose of the drug in use or add unused anti-PD drugs with different mechanisms of action. The dose can be increased or the drug can be added according to clinical symptoms (tremor or rigidity and hypokinesia are prominent) and which drug has a relatively low dose or is relatively more sensitive to treatment among the multiple drugs in use.

Freezing gait is the most common cause of falls in PD patients, which is prone to occur when changing body positions such as standing up, taking steps and turning around. There is currently a lack of effective treatment measures. Adjusting the drug dose or adding drugs occasionally works. Some patients may respond to increasing the dose of compound levodopa or adding MAO-BI and amantadine. In addition, adaptive motor rehabilitation and suggestive therapy, such as gait and balance training, active adjustment of the body's center of gravity, stepping, walking with large steps, visual cues (ground lines, regular patterns or laser beams), listening to commands, listening to music or clapping to walk or cross objects (real or imaginary), etc. may be beneficial. Use a walker or even a wheelchair when necessary and take good protection. With the development of artificial intelligence technology, smart wearable devices and virtual reality technology have brought benefits in improving postural balance disorders and freezing gait.

2. Treatment of movement complications

Motor complications (symptom fluctuations and dyskinesias) are common symptoms in the middle and late stages of PD, which seriously affect the quality of life of patients and bring more difficult problems to clinical treatment. Drugs or methods that provide continuous dopaminergic stimulation (CDS) can delay and treat motor complications. Adjusting the frequency and dosage of medication or adding drugs may improve symptoms, and surgical treatments such as deep brain stimulation (DBS) are also effective.

Treatment of symptom fluctuations (Figure 2): Symptom fluctuations mainly include end-of-dose deterioration and on-off phenomenon.

(1) Treatment methods for end-of-dose deterioration include:

① Avoid the influence of diet (including protein) on the absorption of levodopa and its passage through the blood-brain barrier. Compound levodopa should be taken 1 hour before or 1.5 hours after meals. Adjusting the protein diet may be effective.

② Do not increase the total daily dose of compound levodopa, but appropriately increase the number of doses per day and reduce the dose each time (on the premise that motor symptoms can still be effectively improved).

③ The compound levodopa is changed from regular release to sustained release tablets to prolong the duration of action. It is more suitable for the early onset of end-of-dose deterioration, especially when it occurs at night, but the dose needs to be increased by 20% to 30%. The new levodopa/carbidopa sustained-release capsule can quickly reach and maintain blood levodopa concentration for a long time, reduce the number of doses, shorten the "off" period, and reduce symptom fluctuations. Therefore, the treatment of symptom fluctuations with levodopa/carbidopa sustained-release capsules is evaluated as effective and clinically useful.

④Add long half-life DAs that produce CDS in the striatum. If one of the DAs has been used and adverse reactions or reduced efficacy occur, try another one.

⑤Add COMTI which produces CDS in the striatum.

⑥Add MAO-BI.

⑦The adenosine A2 receptor antagonist istradefylline was evaluated as possibly effective in treating symptom fluctuations and may be clinically useful.

⑧ Bilateral subthalamic nucleus-DBS and globus pallidus internus (GPi)-DBS were evaluated as effective in treating symptom fluctuations. Compared with unilateral thalamic and subthalamic nucleus lesions and unilateral thalamic stimulation, unilateral globus pallidus lesions have more evidence to improve symptom fluctuations.

(2) The methods for dealing with the on-off phenomenon are:

① Use non-ergot DAs with long half-lives, among which pramipexole, ropinirole, and rotigotine have relatively sufficient evidence. The blood concentration of DAs sustained-release tablets once a day is more stable than that of regular-release tablets, and may improve the "on-off" phenomenon more satisfactorily and have higher compliance. For example, ropinirole sustained-release tablets can reduce the "off" period for a longer period of time compared to regular-release tablets.

② For patients with severe "off period" who cannot be improved by oral medications, continuous subcutaneous injection of apomorphine or levodopa intestinal gel infusion can be considered.

③Surgical treatment (subthalamic nucleus-DBS or GPi-DBS).

Figure 2 Principles of treatment for symptom fluctuations in Parkinson's disease patients

2. Treatment of dyskinesia (Figure 3): Dyskinesia includes peak-dose dyskinesia, biphasic dyskinesia and dystonia.

(1) The treatment for peak-dose dyskinesia is:

① Reduce the dose of compound levodopa each time. If end-of-dose phenomenon occurs, increase the number of doses per day.

② If the patient is using compound levodopa alone, the dosage can be appropriately reduced, and DAs or COMTI can be added at the same time.

③Add amantadine or amantadine extended-release tablets. The latter dosage form is currently the only oral drug approved for the treatment of levodopa-related dyskinesia.

④Add atypical antipsychotics such as clozapine.

⑤ If you are using compound levodopa sustained-release tablets, you should switch to regular-release tablets to avoid the cumulative effect of sustained-release tablets.

(2) The treatment methods for biphasic dyskinesia (including initial and final dyskinesia) are as follows: a. If you are using compound levodopa sustained-release tablets, you should switch to regular-release tablets, preferably water solvents, which can effectively relieve initial dyskinesia. b. Adding DAs with long half-lives or adding COMTI that prolongs the plasma elimination half-life of levodopa and increases the area under the curve (AUC) can relieve final dyskinesia and may also help improve initial dyskinesia.

(3) Dystonia includes morning dystonia, off-phase dystonia and on-phase dystonia.

① The treatment for morning dystonia is: a. Take compound levodopa sustained-release tablets or DAs before going to bed. b. You can also take compound levodopa water solution or regular release before getting up.

② The treatment methods for "off" dystonia are: a. Increase the dose or frequency of compound levodopa. b. Add DAs, COMTI or MAO-BI.

③ The treatment methods for "on" dystonia are: a. Basically the same as the treatment methods for peak-dose dyskinesia. b. If drug adjustment is ineffective, botulinum toxin injection can be performed under the guidance of electromyography.

(4) Treatment of drug-resistant dyskinesia: Levodopa/carbidopa intestinal gel preparations, subthalamic nucleus-DBS and GPi-DBS surgery can be beneficial, and subcutaneous injection of apomorphine can also be used. Other drugs for the treatment of dyskinesia that are currently under clinical research mainly act on non-dopamine pathways such as serotonergic, glutamatergic, γ-aminobutyric acid and noradrenergic pathways.

Figure 3 Principles of treatment for dyskinesia in patients with Parkinson's disease

Treatment of non-motor symptoms

The non-motor symptoms of PD involve many types, mainly including sleep disorders, sensory disorders, autonomic dysfunction, and mental and cognitive disorders. Non-motor symptoms may occur throughout all stages of PD. Some non-motor symptoms, such as hyposmia, rapid eye movement sleep behavior disorder (RBD), constipation, and depression, may appear earlier than motor symptoms. Non-motor symptoms can also fluctuate with motor fluctuations. Non-motor symptoms seriously affect the patient's quality of life. Therefore, it is necessary to manage the patient's non-motor symptoms while managing the motor symptoms of PD patients.

1. Treatment of sleep disorders

60%~90% of patients suffer from sleep disorders, which are the most common non-motor symptoms and one of the common nocturnal symptoms of PD.

Sleep disorders mainly include insomnia, RBD, excessive daytime sleepiness (EDS) and restless legs syndrome (RLS); about 50% or more of patients have RBD. The first treatment for RBD is prevention. If the attacks are frequent, clonazepam or melatonin can be given before bedtime. Clonazepam increases the risk of falls and is generally not the first choice.

Insomnia and sleep fragmentation are the most common sleep disorders. First of all, we should rule out anti-PD drugs that can affect nighttime sleep, such as selegiline and amantadine, which can cause insomnia, especially for those who take them in the evening. First of all, we need to correct the medication time. Selegiline should be taken in the morning and noon, and amantadine should be taken before 4 pm. If there is no improvement, the dosage should be reduced or even stopped. If it is not related to the drug, it is mostly related to the nocturnal movement symptoms of PD, or it may be caused by the primary disease.

If it is related to the patient's nocturnal motor symptoms, it is mainly because the nighttime blood concentration of dopaminergic drugs is too low, so adding DAs (especially sustained-release tablets), compound levodopa sustained-release tablets, and COMTI can improve the patient's sleep quality. If it is EDS, it is necessary to consider whether there is a nocturnal sleep disorder. RBD and insomnia patients often have EDS. In addition, it is also related to the use of anti-Parkinson's disease drugs DAs or levodopa.

If the patient becomes drowsy after each dose, it indicates an overdose of the drug, and reducing the dose appropriately can help improve EDS. If this does not improve the condition, another DAs can be used or levodopa sustained-release tablets can be replaced with regular-release tablets, which may improve the condition. Selegiline can also be tried.

The psychostimulant modafinil can be used for patients with refractory EDS. Parkinson's disease patients are also often accompanied by RLS, and DAs are recommended for treatment. DAs such as pramipexole, ropinirole and rotigotine are very effective when used within 2 hours before falling asleep, or compound levodopa can also be effective.

2. Treatment of sensory disorders

The most common sensory disturbances include hyposmia, pain or numbness. More than 90% of patients have hyposmia, which often occurs many years before motor symptoms, but there is currently a lack of effective measures to improve olfactory disorders.

40% to 85% of PD patients suffer from pain. The clinical manifestations and potential causes of pain vary. Musculoskeletal pain is considered the most common. Pain can be caused by the disease itself or by concomitant bone and joint lesions. The first step in pain treatment is to optimize dopaminergic drugs. In particular, for pain with fluctuating symptoms, if the pain or numbness during the "on" period is reduced or disappears after anti-PD drug treatment and reappears during the "off" period, it indicates that it is caused by PD. Dopaminergic drug treatment can be adjusted to prolong the "on" period. About 30% of patients can relieve pain after dopaminergic drug treatment. Otherwise, it is caused by other comorbidities or causes, and corresponding treatment can be given, such as non-opioid (acetaminophen and nonsteroidal anti-inflammatory drugs) and opioid analgesics (oxycodone), anticonvulsants (pregabalin and gabapentin) and antidepressants (duloxetine).

Musculoskeletal pain is usually treated with nonopioid and opioid analgesics, and neuropathic pain is treated with anticonvulsants and antidepressants.

3. Treatment of autonomic dysfunction

The most common autonomic dysfunctions include constipation, urinary disorders, and positional hypotension. For constipation, adequate intake of fluids, fruits, vegetables, cellulose, or other mild laxatives, such as lactulose, Longhui pills, and rhubarb tablets, can improve constipation; gastric motility drugs, such as domperidone and mosapride, can also be added; exercise should be increased. Anticholinergic drugs need to be discontinued.

For the treatment of urinary frequency, urgency and urge incontinence in urinary disorders, peripheral anticholinergic drugs such as oxybutynin, propantheline bromide, tolterodine and scopolamine can be used;

For patients with detrusor areflexia, cholinergic preparations are given (but they should be used with caution as they will aggravate the motor symptoms of PD); if urinary retention occurs, intermittent clean catheterization should be adopted. If it is caused by prostatic hyperplasia, surgical treatment can be performed if necessary in severe cases.

Patients with postural hypotension should increase their salt and water intake; keep their heads elevated when sleeping, rather than lying flat on their backs; wear stretch pants; and do not stand up quickly from a lying or sitting position. Midodrine is the first choice for treatment and is the most effective; droxidopa and domperidone can also be used.

4. Treatment of mental and cognitive disorders

The most common mental and cognitive disorders include depression and/or anxiety, hallucinations and delusions, impulsive compulsive behaviors, cognitive impairment and dementia. First, it is necessary to distinguish whether it may be induced by anti-PD drugs or caused by the disease itself. If it is the former factor, the following anti-PD drugs should be gradually reduced or discontinued according to the probability of being most likely to be induced: anticholinergics, amantadine, MAO-BI, DAs; if it is still necessary, finally reduce the dose of compound levodopa, but be alert to the possible consequences of aggravating PD motor symptoms. If the effect of drug adjustment is not ideal, it may indicate the latter factor, and symptomatic medication should be considered.

1. Depression, anxiety and apathy: About 35% of patients suffer from depression and 31% suffer from anxiety, among which depression and anxiety are the most common. Depression can manifest as "off" depression or have no clear correlation with motor symptoms. Treatment strategies include psychological counseling, drug intervention and repetitive transcranial magnetic stimulation (rTMS).

When depression affects the quality of life and daily life, DAs, antidepressants including serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants (TCAs) are added. Among DAs, pramipexole and SNRIs venlafaxine have sufficient evidence; among TCAs, nortriptyline and desipramine have less evidence to improve depressive symptoms, but they have adverse reactions such as cholinergic and arrhythmic reactions, and are not recommended for elderly patients with cognitive impairment.

It should be noted that SSRIs may occasionally aggravate motor symptoms in some patients; daily doses of citalopram above 20 mg may cause long QT intervals in the elderly and should be used with caution.

Common treatments for PD with anxiety include antidepressants and psychotherapy;

For PD with apathy, DAs such as piribedil and the cholinesterase inhibitor rivastigmine may be useful.

2. Hallucinations and delusions: The incidence of hallucinations and delusions in PD is 13%~60%, among which visual hallucinations are the most common.

First, we should rule out anti-PD drugs that may induce psychiatric symptoms, especially anticholinergic drugs, amantadine and DAs. If drug induction is ruled out, it may be caused by the disease itself, so symptomatic treatment is given. Clozapine or quetiapine is recommended. Clozapine has a 1% to 2% chance of causing agranulocytosis, so blood cell counts need to be monitored. Therefore, quetiapine is commonly used in clinical practice.

The selective serotonin 2A inverse agonist pimavanserin is also used to treat psychiatric symptoms associated with PD because it does not aggravate motor symptoms.

Other antipsychotics are not recommended because they can aggravate motor symptoms;

For irritable states, lorazepam and diazepam are effective.

All psychotropic drugs are not recommended for use in patients with PD and dementia.

3. Impulsive-compulsive behaviors (ICBs): including impulse control disorders (ICDs), dopamine dysregulation syndrome (DDS) and stereotyped behaviors. ICDs include pathological gambling, compulsive shopping, hypersexuality, compulsive eating, etc.; DDS is a neuropsychiatric disorder related to dopaminergic drug abuse or addiction, and patients experience severe but tolerable dyskinesia, anxiety during the "off" period, and cyclical mood changes related to dopamine drug addiction; stereotyped behaviors are repetitive, purposeless, and meaningless stereotyped motor behaviors similar to obsessive-compulsive disorder, such as driving or walking aimlessly, repeatedly cleaning or clearing things, etc., and this stereotyped behavior is usually related to the previous occupation or hobby.

Treatment of ICDs can reduce the dosage of DAs or stop using them. If DAs must be used, a sustained-release formulation can be tried. Topiramate, zonisamide, antipsychotics (quetiapine, clozapine), and amantadine may be effective. Opioid antagonists (naltrexone and nalmefene) may be useful, but further research is needed. Cognitive behavioral therapy (CBT) can also be tried.

Treatment of DDS can improve symptoms by reducing or stopping dopaminergic drugs. Short-term low-dose clozapine and quetiapine may be helpful in some cases. Continuous levodopa infusion and subthalamic nucleus-DBS can improve symptoms in some patients.

Severe dyskinesias and "off" mood problems can be improved with subcutaneous apomorphine.

For the treatment of stereotyped behaviors, reducing or discontinuing dopaminergic drugs may be effective, but a balance must be struck between the control of stereotyped behaviors and the worsening of motor symptoms; clozapine and quetiapine, amantadine, and rTMS can improve symptoms, but further verification is needed.

There is still a lack of effective evidence-based intervention methods for the treatment of the above three types of ICBs, and clinical treatment is rather difficult, so prevention is the priority.

4. Cognitive impairment and dementia: 25% to 30% of PD patients are accompanied by dementia or cognitive impairment. In clinical practice, anti-PD drugs that may affect cognition, such as the anticholinergic drug trihexyphenidyl, must be excluded first. If drug-induced factors are excluded, cholinesterase inhibitors can be used. Rivastigmine has sufficient evidence and is clinically useful; donepezil and galantamine have limited evidence and may be clinically useful.

* Surgery

PD responds well to drug treatment in the early stages, but as the disease progresses, drug efficacy decreases significantly, or when severe symptom fluctuations or dyskinesias occur, surgical treatment can be considered. The main surgical methods are nerve nucleus destruction and DBS. DBS has become the main surgical option at present because it is relatively non-invasive, safe, and controllable.

It should be emphasized that although surgery can significantly improve motor symptoms, it cannot cure the disease; drug treatment is still required after surgery, but the dosage can be reduced, and the patient needs to be optimized and the stimulation parameters adjusted in a timely manner. Patients with Parkinson's plus syndrome who are not primary PD are not responsive to surgery and are contraindicated for surgery.

Surgery has a good effect on limb tremor and/or muscle rigidity, but it has little effect or is ineffective on axial symptoms such as severe speech and swallowing disorders and gait and balance disorders. In addition, it has no clear effect on some non-motor symptoms such as cognitive impairment, and may even worsen them.

*Rehabilitation and exercise therapy

It is helpful to improve the motor and non-motor symptoms of PD and even to delay the progression of the disease. PD patients often have axial symptoms such as gait disorders, postural balance disorders, language and (or) swallowing disorders, which are rarely effective for drugs but can benefit from rehabilitation and exercise therapy. Therefore, rehabilitation therapy is recommended for the entire course of PD patients.

Carry out appropriate rehabilitation or sports training according to different movement disorders, such as walking, Tai Chi, yoga, dance, aerobic exercise, resistance training, etc.

Effective PD rehabilitation therapy includes: physical and exercise therapy, occupational therapy, speech and language therapy, and swallowing therapy. It should be noted that safety comes first when conducting rehabilitation and exercise therapy.

It is necessary to develop individualized and adaptive rehabilitation and exercise training plans based on the different characteristics of different patients; at the same time, long-term compliance needs to be ensured. If patients can persist in doing so every day, it will help improve their ability to take care of themselves, improve their motor function, and extend the effectiveness of the drug.

*Psychological intervention

Psychological intervention, especially cognitive training and CBT, provides a feasible non-drug treatment option. Neuropsychiatric symptoms of PD patients should be treated with effective psychological intervention, with equal emphasis on drug use, to alleviate physical symptoms, improve psychological and mental state, and achieve better treatment results.

* Nursing care: Scientific nursing is very important to maintain the patient's quality of life.

Scientific care can play a certain auxiliary therapeutic role in effectively controlling the disease and improving symptoms; at the same time, it can more effectively prevent possible accidents such as aspiration or falls.

Comprehensive care is provided for motor symptoms and non-motor symptoms, including drug care, dietary care, psychological care and rehabilitation training. Patients are informed of the usage and precautions of drugs, which is conducive to standardizing drug use and avoiding the occurrence of adverse drug reactions; targeted dietary plans are customized to improve patients' nutritional status and symptoms such as constipation; patients' psychological state is assessed in a timely manner, and positive guidance is given to regulate patients' negative emotions and improve their quality of life. In cooperation with family members, patients are urged to undergo rehabilitation training to maintain good motor function and improve their self-care ability.

*Artificial intelligence and mobile technology

1. Telemedicine: It makes medical treatment more convenient, thereby increasing the frequency of interaction between doctors and patients, and helping doctors to comprehensively assess the condition and guide treatment.

2. Wearable devices: On the one hand, they can objectively evaluate and monitor symptoms, which helps to accurately assess the condition and formulate individualized plans; on the other hand, they can be used as an auxiliary treatment to improve the patient's quality of life, such as anti-shake spoons to assist eating, and visual/auditory prompts to improve freezing of gait.

3. Smartphone applications: are conducive to the collection of patient information, condition assessment and patient education.

4. Virtual reality technology can be used for rehabilitation training.