Drug-induced parkinsonism is a secondary iatrogenic Parkinsonian syndrome that develops against the background of taking a number of pharmacological drugs. The clinic simulates Parkinson’s disease. Features are subacute debut, initially symmetrical nature of manifestations, rapid progression. Diagnostics includes a study of drug history, assessment of neurological status, instrumental examinations (MRI, EEG). It is recommended to cancel the pharmaceutical product that provoked drug parkinsonism. Cholinolytics, vitamins are prescribed, and antiparkinsonian drugs are prescribed according to indications.
ICD 10
G21.1 Other forms of secondary drug-induced parkinsonism
General information
According to the frequency of occurrence in the general structure of Parkinsonism, drug-induced parkinsonism (DIP) ranks second after Parkinson’s disease. According to various estimates, DIP accounts for 23-37% of all diagnosed cases of parkinsonism. Drug-induced parkinsonism is the most common variant of neuroleptic syndrome and occurs in 10-25% of patients taking neuroleptics. The disease occurs mainly among patients aged 60-80 years, more often in women. In modern neurology, the diagnosis of DIP is an urgent problem, since in some cases its manifestations are mistakenly interpreted as a new pathology or as a consequence of natural aging processes. According to statistics, the appointment of antiparkinsonian drugs instead of canceling parkinsonism-provoking therapy occurs in 36% of cases.
Causes
The etiofactor that causes the drug variant of Parkinsonian syndrome is the intake of pharmaceuticals that have a blocking effect on dopamine receptors. In most cases, DIP is associated with treatment with neuroleptic drugs. The list of other medications that can provoke drug-induced parkinsonism is quite wide. It includes:
- Sympatholytics. Sympatholytic agents of central action (tetrabenazine) are used in the therapy of hyperkinesis, hypertension. The DIP-provoking effect is caused by depletion of the dopamine content in the vesicles of synaptic endings.
- Metoclopramide. It is widely prescribed as an antiemetic. It has a structural similarity with chlorpromazine, which causes the blockade of postsynaptic dopamine receptors.
- Calcium antagonists (flunarizine, cinnarizine). Taking drugs is accompanied by blocking of dopamine receptors, a decrease in the reserves of the mediator in the presynaptic terminals. As a result, a deficiency of dopamine transmission develops.
- Anticonvulsants. Drug parkinsonism on the background of antiepileptic therapy is more associated with the use of valproates, associated with their toxic effects on dopaminergic structures. Much less often, DIP is observed when taking carbamazepine, the mechanism of its development remains unclear.
- Other pharmaceuticals. Individual cases of DIP have been described when taking amiodarone, levostatin, fluoxetine, phenytoin, clopamide, promethazine. A complication of therapy occurs with prolonged administration, high dosages of these drugs.
Along with the immediate causes of DIP, there are factors that increase the likelihood of its development. These include the presence of extrapyramidal disorders in the anamnesis, hereditary predisposition, depression, HIV infection. The high-risk group includes elderly patients, women, patients with organic pathology of the brain (the consequences of a stroke, traumatic brain injury, degenerative diseases).
Pathogenesis
Each of the above drugs has a blocking effect on the dopaminergic system of the brain. The predominant mechanisms are blocking of striatum D2 receptors, violation of dopamine release from presynaptic terminals. The result is the dominance of acetylcholine effects that excessively activate the caudate nucleus. The latter has a retarding effect on the motor sphere, which is clinically manifested by oligobradykinesia — a decrease in the number, speed, amplitude of movements. Studies have shown that the clinical symptoms of DIP develop when more than 75% of D2 receptors are blocked.
A certain pathogenetic role is assigned to latent dopamine deficiency, manifesting with additional dopamine-blocking effects of the drug being taken. Its presence is confirmed by the progression of Parkinsonian symptoms in 30% of cases after discontinuation of the provoking drug.
Symptoms
The timing of the DIP debut from the beginning of provoking therapy varies from several days to months. In 90% of cases, drug-induced parkinsonism debuts in the first three months of treatment. Since recognition of the initial symptoms is difficult, the patient continues taking the provocative drug, which leads to a progressive increase in symptoms. The DIP clinic is similar to the manifestations of Parkinson’s disease. The most frequent, and in some cases the only clinical symptom is hypokinesia. There is a general motor slowness, a decrease in facial expressions (hypomimia), the absence of friendly movements (achaeirokinesis), sluggish gestures, micrography, shuffling gait. There may be solidification during walking. Hypokinesia is combined with muscle rigidity.
A typical resting tremor is not observed in all patients. Neuroleptic parkinsonism is often accompanied by pronounced postural-kinetic trembling involving the extremities, chin, and perioral region. Sometimes there is an isolated perioral tremor. Oral dyskinesia is characteristic of DIP caused by metoclopramide. Postural instability is expressed slightly, observed mainly in cinnarizine parkinsonism. Drug-induced parkinsonism, provoked by valproates, is sometimes combined with hearing loss, cognitive disorders.
Complications
The disease worsens the condition of elderly patients. Postural instability leads to falls, complicated by various injuries, often fractures due to age—related osteoporosis. The lack of timely diagnosis causes the progression of motor dysfunction up to the restriction of independent movement. The low mood background and isolation accompanying DIP can be complicated by the development of depression.
Diagnostics
Diagnostic difficulties are associated with the age category of patients. In old age, neurodegenerative processes with extrapyramidal disorders are widespread, which complicates the differential diagnosis of Parkinsonian syndrome. Pharmacological history and features of clinical manifestations are of key importance in the diagnosis. The general scheme of examination of patients includes:
- Collecting anamnesis. By interviewing and studying medical documentation, a neurologist identifies the presence of a hereditary predisposition, diagnosed organic cerebral pathology. The pharmacotherapy prescribed to the patient is being analyzed, but the presence of a potentially dangerous drug in it should not be interpreted unambiguously.
- Objective inspection. Confirms symmetrical oligobradykinesia, determines the characteristic rigidity of muscles, tremor, instability in the Romberg pose. In the presence of organic pathology, it is possible to identify the corresponding concomitant symptoms.
- Instrumental research. Electroencephalography is prescribed. Assessment of the state of cerebral hemodynamics is carried out using REG, ultrasound, duplex scanning of cerebral vessels. Morphological changes in tissues are determined during MRI of the brain. The detection of vascular, organic changes does not exclude the diagnosis of DIP.
Drug-induced parkinsonism is differentiated with Parkinson’s disease, other forms of secondary Parkinsonian syndrome (vascular, post-infectious, post-traumatic). The distinctive features of DIP are subacute onset with subsequent progression of manifestations, stabilization or regression of symptoms after withdrawal of the provoking drug, symmetry of motor dysfunction, combination of Parkinsonian symptoms with other forms of drug dyskinesia (for example, akathisia), endocrine disorders (hyperprolactinemia, amenorrhea). Drug-induced parkinsonism should be excluded in patients with dementia with Lewy bodies and Wilson’s disease, who are prescribed psychotropic medications when the disease manifests from mental disorders.
Treatment
The basis of DIP therapy is the abolition of the provoking pharmacological agent. If it is impossible to cancel the drug, the issue of reducing the dosage or replacing it with a drug of the same pharmacological group with a less pronounced dopamine-blocking effect is resolved. For example, a typical neuroleptic can be replaced with an atypical one. Further treatment is carried out with the appointment of the following groups of medications:
- Holinolytics. They are necessary if it is impossible to completely cancel the provoking drug, the presence of concomitant dyskinesia, akathisia. Preference is given to biperiden, which has a more selective effect on cerebral M1-cholinergic receptors and reduces the risk of peripheral cholinolytic side effects (arterial hypotension, tachycardia, dry mouth).
- Antiparkinsonian drugs. Dopamine receptor agonists and levodopa pharmaceuticals accelerate the regression of parkinsonian symptoms. They are not prescribed to patients with mental disorders, because they can increase psychotic symptoms. Antiparkinsonian treatment is mandatory in case of progression of parkinsonism after discontinuation of the provoking medication.
- Vitamins. Vitamin B6 helps to reduce extrapyramidal symptoms. In the therapy of neuroleptic parkinsonism, vitamin E is used along with other antioxidants.
Prognosis and prevention
Withdrawal of the drug leads to a regression of symptoms for several months, sometimes the reverse development of symptoms lasts more than a year. In 30% of patients, stabilization or further progression of Parkinsonian manifestations is noted, which is due to the previous latent course of the degenerative process. Individual cases of neurodegenerative pathology development a few months and years after undergoing DIP are described. The main measure of prevention of DIP is an adequate selection of the drug, its dosages and duration of therapy. For elderly people, it is better to prescribe domperidone as an antiemetic drug, which is unable to penetrate the BBB. The use of antipsychotics should be avoided in elderly patients with anxiety-depressive symptoms, in cases of low effectiveness of sedatives and antidepressants, atypical antipsychotics should be recommended.
