Parkinson’s disease (PD) is a chronic progressive disease in which the main chemical pathology is the death of nigrostriatal neurons and the inability of their dense parts to synthesize dopamine (DA), resulting in an imbalance between acetylcholine (A ch) and DA function in the striatum. Since the introduction of levodopa in the 1960s to treat PD with significant symptomatic improvement, several drugs have been developed in recent years to treat PD, including monoamine oxidase (MAO) inhibitors, dopamine agonists, catechol O-methyltransferase inhibitors, and glutamine release inhibitors. etc. However, levodopa/peripheral dopamine decarboxylase inhibitor (L-dopa/PDI) therapy remains the best choice for symptomatic treatment of PD, usually providing satisfactory symptom control for about 6 years or longer, followed by progressive symptom progression. Many factors can influence the long-term prognosis of the disease, including the choice of drug, when to administer it, and the dose and dosing sequence. In this article, we first discuss the clinical features of early Parkinson’s disease and then propose treatment strategies for early Parkinson’s disease based on evidence from evidence-based medicine.
The three main signs of Parkinson’s disease are bradykinesia, bradykinesia and resting tremor. In the early stages of the disease, these manifestations are not very obvious. As the disease progresses, the patient’s symptoms generally become more pronounced from a unilateral perspective. Early signs of the disease include decreased upper extremity oscillation during walking, asymmetric gait, decreased flexibility, and resting tremor in about 75% of cases. Early signs of the disease include decreased blinking, lack of facial expressions, decreased movements and impaired postural reflexes. Changes in personality, speech patterns and writing may indicate the onset of PD. Dystonia is also an early manifestation, especially in young patients. Depression and anxiety are common in the early stages of the disease, even before the onset of motor symptoms, and have a significant impact on the patient’s quality of life. Autonomic symptoms of varying degrees are also common, and constipation is one of the manifestations.
2.The early diagnosis of Parkinson’s disease depends on symptoms, signs and other clinical manifestations, and PD should be considered if there are three or more of the following: ① onset: slow movement and resting tremor of one or more limbs; ② obvious unilateral distribution of onset; ③ leadpipe or gear-like straightening, accompanied by reduced movement of the face, trunk or limbs, abnormal postural reflexes, etc.; ④ response to L-dopa treatment within 2 months Good response (improvement of 25% or more) within 2 months of L-dopa treatment.
Primary tremor is most often confused with Parkinson’s disease, but in patients with primary tremor, the facial expression is normal, the speed of movement is normal, and there is no gait disturbance, so primary tremor is a motor tremor, not a resting tremor, which is the most common form of Parkinson’s disease. The differentiation from other secondary Parkinson’s syndromes can be made from the history and signs.
3.Treatment of early Parkinson’s disease.
(1) Non-pharmacological treatment Encourage patients to do more active exercises and participate in more social activities to prevent premature decline. Diet: carbohydrate-based in the morning and lunch, protein-based in the evening.
(2) Drug therapy.
(1) We will first discuss several issues concerning the drug treatment of Parkinson’s disease.
Does Selegiline have a neuroprotective effect and slow down the natural progression of PD? The available clinical data confirm that Selegiline can delay the need for L-dopa/PDI for 9-12 months in early stage Parkinson’s patients, and experimental data and clinical trials suggest that Selegiline has a neuroprotective effect.
②Is it beneficial to save L-dopa dosage? L-dopa has been shown to be effective in the symptomatic treatment of PD, but the possibility of accelerated neuronal degeneration cannot be ruled out. In fact, good symptomatic efficacy may mask its adverse effects on long-term prognosis; available evidence suggests that L-dopa may accelerate disease progression and cause fluctuations in symptoms and dyskinesia, so L-dopa dosage saving may be necessary.
(iii) Do dopamine agonists have neuroprotective effects? Bromocriptine can scavenge free radicals, such as hydroxyl radicals and superoxide radicals, and inhibit lipid peroxidation, which has a powerful antioxidant effect, more significant than vitamin E and vitamin C. Pretreatment of mice with bromocriptolide completely protected them from the neurotoxic effects of 6-hydroxydopamine. Pergolide increased superoxide dismutase activity and helped to protect neurons. In addition to these direct antioxidant effects, receptor agonists stimulate D-2 self-receptors, reducing the firing rate of neurons, reducing endogenous dopamine conversion, and thus reducing free radical production. The number of striatal neurons was reduced by 3.5% in the experimental group and by 26.8% in the control group (P < 0.01), but it is not clear which mechanism was responsible.
The analysis of the above evidence can help to propose a rational strategy for the pharmacological treatment of Parkinson’s disease.
2) Basic principles of pharmacotherapy. Detailed assessment of each patient’s signs and symptoms and their impact on life is necessary to determine the goals of treatment. The advantages and disadvantages of any type of treatment must be considered before starting it. Gradually adjust the dosage of drugs according to the needs of the disease. Symptomatic drugs are started in small doses and increased slowly to reduce the incidence of adverse effects. Only one drug is adjusted at a time, and the optimal dose is the lowest dose that allows the patient to have adequate physiological function.
4, Parkinson’s disease early drug treatment strategy for young patients in the early treatment should emphasize its long-term effects. These patients are expected to have a longer disease duration, often with chronic disability due to disease progression, and are more likely to have fluctuating symptoms and movement disorders. In older patients, with a shorter expected duration of disease, the emphasis is on providing adequate short-term symptom improvement with the least possible adverse drug effects. Based on theoretical speculation, basic science, animal model studies, and available clinical trials, this paper proposes an early treatment strategy for Parkinson’s disease.
If a drug has a neuroprotective effect in PD patients, it should be used once the diagnosis of PD is established. This paper discusses the possible neuroprotective effect of sellegrin. The younger the patient, the more important it is to intervene early to slow disease progression, and therefore the more important it is to start sildegiline as soon as the diagnosis is established.
Once the diagnosis is made, symptomatic treatment is usually given only when the patient is functionally disabled, mainly because of the possible adverse effects of long-term L-dopa/PD I treatment. The choice of drug is determined by the patient’s clinical presentation. If the tremor is predominant, anticholinergic drugs are used initially, and the tremor is well controlled in nearly 50% of patients. However, it does not improve the slow movement or myotonicity. If an anticholinergic drug is not effective, other similar drugs may be tried. Adverse cognitive effects, such as confusion and hallucinations, are relatively common, especially in older patients.
If the symptoms are mainly bradykinesia, bradykinesia, gait abnormalities, dopaminergic drugs (receptor agonists, L-dopa/PDI) may be used. Start with small doses and gradually increase them. If bradykinesia and tonicity are reduced but tremor persists, an anticholinergic drug may be added.
This regimen is less likely to result in symptom fluctuations and dyskinesia, and may reduce the dosage of L-dopa/PDI. In patients with dementia or elderly patients with a short life expectancy, who are prone to adverse reactions to receptor agonist therapy, direct L-dopa/PDI is recommended, usually starting with a receptor agonist in patients under 65 years of age, direct L-dopa/PDI over 70 years of age, and between 65 and 70 years of age depending on the patient’s general health and cognitive status.
There is reason to recommend the use of dopaminergic agonists as soon as possible after diagnosis is made, especially in younger patients. There is growing evidence of neuroprotective effects of receptor agonists, and no evidence of long-term adverse effects. Low doses are started and slowly increased until symptoms are controlled or intolerable adverse effects occur. The most common are nausea, postural hypotension, hallucinations, and insomnia. Postprandial dosing may reduce nausea, preceded by gastrofacial if necessary.
L-dopa/PDI controlled-release tablets are easy to take and provide a more significant long-term improvement in the patient’s daily life than regular tablets. The dose of L-dopa can be adjusted as needed, with most patients having good symptom control for 3-5 years or more at doses of 400-600 mg/d. Higher doses for complete symptom control should be avoided. Postprandial dosing may reduce nausea and may be preceded by gastroflucan if necessary.
Most patients with bradykinesia and bradykinesia are significantly reduced within a few weeks after taking L-dopa/PDI, but if the improvement is not significant, the cause should be carefully analyzed. There may be an inappropriate choice of drug, a low dose of L-dopa or a wrong diagnosis. Patients often believe that L-dopa/PDI is ineffective because there is no reduction in tremor, but in fact L-dopa/PDI is effective in only about 50% of patients with tremor. Patients with significant bradykinesia and tonic symptoms that do not improve with L-dopa/PDI may have an atypical Parkinson’s syndrome other than PD.
COMT inhibitors reduce peripheral L-dopa metabolism and prolong its half-life, reduce fluctuations in L-dopa concentrations, increase and prolong L-dopa/PD I efficacy, improve patient motor function, and reduce L-dopa/PDI dose. It is usually well tolerated. Whether early use improves the long-term prognosis of the patient is not known.
If the patient has severe tremor but does not respond to standard medications (L-dopa/PDI, anticholinergics), clozapine may be used, starting at a low dose (< 12.5 mg/d) to reduce acute adverse effects, and weekly blood counts due to the possibility of granulocyte deficiency.