The clinical manifestations of Parkinson’s disease include four major motor symptoms: tremor, muscle rigidity, bradykinesia, postural gait disorder and non-motor symptoms such as excessive sweating, drooling, depression, pain, sleep disturbance, abdominal distention, and bowel and urinary disorders. Parkinson’s disease is not curable. Not being curable does not mean that it cannot be treated, and patients can maintain a better quality of life with medication to maintain and restore their ability to work. The goal of Parkinson’s disease treatment is to delay progression (neuroprotection), improve motor symptoms and non-motor symptoms, and prevent and treat complications. The principles of Parkinson’s disease treatment are “long flow of water, not full effect” and “the smallest dose to achieve the best effect”.
The goals of Parkinson’s disease treatment are
The first goal is to maintain or restore the ability to work. This is the goal of treatment for young, early-stage Parkinson’s disease patients, who are mostly in stages I and II according to H-Y staging;
The second goal: to maintain or restore the ability to care for oneself. The minimum treatment goal for patients with intermediate to advanced Parkinson’s disease. Most of these patients are in stage III by H-Y staging;
Third goal: to reduce pain and prolong life. Minimum treatment goals for patients with advanced Parkinson’s disease. These patients are mostly in stages IV and V by H-Y staging.
Classification of anti-Parkinson’s disease drugs.
I. Anticholinergic drugs: such as Antan
II. Amantadine
III. compound levodopa: methyldopa, restorative controlled-release tablets
Dopamine receptor agonists: Tysudar, Senfuro (soon to be marketed ropinirole, rotigotine)
V. MAO-B inhibitors: Midolpir, Rexagiline
Sixth, COMT inhibitors: Kotan, Dalinfusion (levodopa and Kotan compound)
Anticholinergic drugs: Antan: Usage 1 to 2 mg three times a day. Mainly for patients with tremor; and for patients without tremor is generally not used, especially in elderly patients with caution (≥ 65 is not recommended, can cause intelligent damage); closed-angle glaucoma and prostatic hypertrophy patients are prohibited.
Amantadine: 100mg , twice daily (before 4pm), central side effects: confusion, hallucinations, insomnia and nightmares, peripheral side effects: reticular cyanosis, ankle edema, dry mouth; blurred vision, withdrawal effect; better effect on muscle rigidity, can reduce allodynia.
L-dopa complex: the most effective symptom control drug, the “gold standard” for the treatment of Parkinson’s disease. Dosage form: Medopa (standard tablet = levodopa + benserazide), Xanax (controlled release tablet = levodopa + carbidopa). Action: Effective in patients of all stages. Treatment principle: It should be started in small doses and increased slowly. The dose used should be individualized and taken before or one hour after meals (animal protein in food can affect the absorption of the drug). It should be used in combination with other drugs in patients with intermediate or advanced disease.
The credo of “cautiously delaying the use of levodopa until it is necessary because of concerns about possible toxicity and consequent acceleration of Parkinson’s disease progression” has become a principle followed by more clinicians. This view is wrong. Epidemiological studies have shown that long-term levodopa treatment prolongs life expectancy in PD, with the average survival of PD patients increasing from <10 years to the current 20 years since levodopa was introduced, and the DATATOP study showed no significant difference in life expectancy between patients treated with levodopa and the overall population. In a long-term follow-up study of more than 934 PD patients over 22 years, it was shown that patients' life expectancy was reduced if levodopa was not given until postural instability developed. Levodopa is the highly effective and best-tolerated anti-Parkinson's disease drug.
Dopamine agonists: drugs currently available in China: Tysudar: 50 mg, 2-3 times a day; Senfuro: 0.25-1.5 mg, 3 times a day; drugs not yet available in China: Ropinirole: (imported ones have completed clinical trials and are ready to be marketed; domestic ones are preparing for clinical trials of new drugs) Rotigotine: (posterior agent, once a day, clinical trials are underway).
Dopamine receptor agonists are effective in the treatment of early Parkinson’s disease. May reduce the incidence of symptom fluctuations and dyskinesia; reduce the dose of levodopa use; may have neuroprotective effects and delay disease progression; improve motor symptoms in PD patients.
Features of Tysudar: 1. Rapid improvement of dyskinesia symptoms and sustained efficacy; 2. Improved alertness; 3. Delayed levodopa use; 4. Delayed levodopa-induced motor complications…
Senflor features: 1. A new generation of non-ergot selective dopamine D2/D3 receptor agonist; 2. Effective in improving motor symptoms in patients with early and late PD; 3. Simultaneous relief of depressive symptoms associated with PD; 4. Effective in delaying and reducing the occurrence and extent of levodopa-related motor complications; 5. Combination of drugs can reduce the dose of levodopa; 6. Easy to use and well-tolerated
B-type monoamine oxidase inhibitors (MAO-BI): first generation: Midopir and Kingspin (already marketed in China); second generation: Resagiline (recently marketed); effects: delay the use of levodopa; improve the fluctuation of symptoms that occur after levodopa treatment; increase and prolong the efficacy of levodopa; reduce the dosage of levodopa; mechanism: increase the content of dopamine in the brain; block the generation of oxygen free radicals.
Catechol-oxygen-site methyltransferase (COMT) inhibitors: Kotan (entacapone 0.2): 0.1~0.2, 3~10 times a day, taken with levodopa preparations; Darinflux (entacapone 0.2+Xinin 0.1), mechanism: increase the bioavailability and duration of action of levodopa without increasing the peak plasma concentration of levodopa. The reduction of methyldopa formation increases the entry of levodopa into the brain through the blood-brain barrier, which stabilizes the levodopa paddle concentration and avoids the side effect of fluctuating symptoms due to the peak concentration.
Late complications of Parkinson’s disease
Movement disorders: end-of-agent phenomenon, heterokinesia, dystonia, gait stiffness, balance disorders
Behavioral/psychiatric: depression, sleep disorders, psychiatric symptoms
Vegetative: upright hypotension, hyperhidrosis, constipation, impotence, urinary incontinence/retention
Treatment strategies for end-of-dose phenomena: continuous levodopa administration; continuous intravenous infusion, continuous enteral administration, controlled release agents; dual controlled release agents, transdermal administration; application of dopamine metabolizing enzyme inhibitors: kodan (Darinflux), midodrine (Kingspin); application of long-acting dopamine receptor agonists: Tysudar, semiflor, ropinirole, rotigotine.
Treatment strategies for allodynia.
Ochronosis occurring during the levodopa peak-effect phase: switch to levodopa controlled-release (restorative); reduce each methyldopa or restorative dose; reduce each levodopa dose while adding dopamine receptor agonists (Tysudar, Senflor); add amantadine 0.1 Bid; add Seroquel, clozapine, zonisamide; DBS surgery.
Dystonia during the end-effect phase of levodopa: increase the number and dose of methyldopa or restraint doses; use methyldopa or levodopa aqueous; MAO-B inhibitors (Midodopa, Kingspin); add dopamine agonists (Tysudar, Senfro); add amantadine; add Sirecon, clozapine or zonisamide; surgery: DBS.
Treatment strategies for dystonia (dystonia)
Painful spasmodic dystonia presenting in the morning : nighttime dose at bedtime (Benadryl), or nighttime long-acting dopamine agonists (Tysudar, Senfuro), methyldopa or levodopa aqueous solvent before waking, local intramuscular injection of botulinum toxin type A for spasticity; surgery: DBS.
Painful spastic dystonia during peak levodopa effect: reduce the dose of methyldopa or restorative at each dose, increase the number of doses, add or increase the dose of dopamine agonists (Tysudar, Senfuro), local injection of botulinum toxin type A in the muscle of painful spasm, add COMT inhibitor (Kodan, Darinflex), use MAO-B inhibitor (Midodrine, Kingspin), surgery:DBS.
Stiffness and falls
Stiffness, difficulty starting/inability to move in starting, traveling, turning or narrow passages, strategies: use auditory, visual stimulation, gait training Droxidopa (100-300 mg three times a day), DBS surgery.
Falls: crutches, wheelchair.
Upright hypotension: stop anti-hypertensive drugs, increase salt intake, prednisone, wear elastic stockings, Midodrine hydrochloride (Tubotone), 2.5-20mg per day; Droxidopa (100-300mg, three times per day): improve gait stiffness and upright hypotension caused by PD
Urinary incontinence and frequency: first perform urodynamic examination: distinguish whether it is unstable bladder, urinary tract obstruction or weak bladder contraction, prostatic hypertrophy, mental abnormality, infection. If it is an overactivity of the detrusor muscle, treat with sernitin. Use bromipyridamole for bladder contraction weakness.
Management of psychiatric symptoms
Psychiatric symptoms are manifested by visual hallucinations, auditory or tactile hallucinations, paranoid delusions; treatment: control the causative factors: infections and metabolic diseases, water-electrolyte imbalance, etc.; discontinue unnecessary non-anti-Parkinsonian drugs: e.g. antidepressants, anxiolytics, sedative-hypnotics; discontinue anti-PD drugs, discontinue in the following order: anticholinergic drugs -amantadine -Discontinue restoratives and switch to methyldopa. Trial of small doses of non-classical antipsychotics: Seroquel, clozapine.
Deep brain stimulation (DBS)
Deep brain electrical stimulation, using brain stereotactic surgery to implant electrodes at a specific location in the brain, can inhibit abnormal electrical activity of neurons through high-frequency electrical stimulation, thus playing a role in controlling symptoms.
Indications for brain pacemaker treatment of Parkinson’s disease
Parkinson’s disease, which is typical of Parkinson’s disease, has been effective with levodopa preparations;
Symptoms are no longer controlled after complete drug therapy or complications such as allodynia or hypoacusis have not improved with drug adjustments;
A history of at least 5 years;
Absence of severe cognitive and psychiatric impairment and brain atrophy;
DBS exclusion criteria
Atypical Parkinson’s syndrome
Poor response to levodopa
Significant dementia
When should DBS surgery be considered?
Difficult motor symptoms despite systematic and complete drug therapy, including: rigidity, tremor, bradykinesia; end-of-dose phenomenon, switching phenomenon; isokinetic disorder; motor fluctuations; refractory tremor
Efficacy of brain pacemakers
Control of the main symptoms of PD: tremor, bradykinesia, rigidity, etc.; similar motor function in the “off” phase of the drug as in the best “on” phase before surgery; reduction of the dose of the drug; reduction of drug-induced “isokinesia” and its duration The reduction of drug dosage; reduction of drug-induced “ochronosis” and its duration; typical Parkinson’s tremor – even if it does not respond to drug treatment; restoration of the patient’s ability to live independently again.
Factors affecting the efficacy of pacemakers
Appropriate patient selection; proper DBS electrode implantation; optimal postoperative management: pacemaker parameter adjustment and medication coordination.
Reasons for suboptimal pacemaker efficacy
Inappropriate patient selection: Parkinson’s superposition syndrome
Incorrect position of DBS electrode implantation
Poor postoperative pacemaker parameter adjustment
Improper adjustment of medications
Postoperative patient management
Optimal symptom control
Minimal side effects
Medication dose reduction
Extended pulse generator battery life
Coordination of electrical stimulation and medication
Clinical effectiveness is influenced by the ideal stimulation parameters and drug therapy
Electrical stimulation may enhance the efficacy of dopaminergic drugs
Allodynia may be exacerbated, especially at the time of initial stimulation
Medications need to be adjusted