Parkinson's disease

Parkinson's disease is an idiopathic, slowly progressive, degenerative disorder of the central nervous system characterized by hypokinesia, muscle rigidity, resting tremor, and postural instability.

Diagnosis is based on clinical data. Treatment is levodopa plus carbidopa, other drugs, and in refractory cases, surgery.

Parkinson's disease affects approximately 0.4% of the population over 40 years of age and 1% over 65 years of age. The average age of onset is about 57 years. Rarely, Parkinson's disease begins in childhood or puberty (juvenile parkinsonism).

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Causes of Parkinson's Disease

In Parkinson's disease, the number of pigmented neurons in the substantia nigra, locus ceruleus, and other catecholaminergic nuclei of the brainstem decreases for an unknown reason. The loss of neurons in the substantia nigra, which are associated with the caudate nucleus and putamen, reduces the amount of dopamine in these structures as well.

Secondary parkinsonism results from loss or suppression of dopamine action in the basal ganglia due to other degenerative diseases, drugs, or exogenous toxins. The most common cause is phenothiazine, thioxanthene, butyrophenone, other dopamine receptor blocking neuroleptics, or reserpine. Less common causes include carbon monoxide poisoning, manganese poisoning, hydrocephalus, organic brain damage (eg, tumors and infarcts involving the midbrain or basal ganglia), subdural hematoma, hepatolenticular degeneration, and idiopathic degenerative disease (eg, striatonigral degeneration, multiple system atrophy). NMPTP (p-methyl-1,2,3,4-tetrachloropyridine) is an experimental drug synthesized during unsuccessful attempts to obtain meperidine. When administered parenterally, it can cause severe irreversible parkinsonism. Parkinsonism is caused by damage to the basal ganglia in encephalitis.

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Symptoms of Parkinson's Disease

In most cases, the symptoms of Parkinson's disease begin gradually, with a resting tremor (like rolling a pill) of one hand. The tremor is slow and rough, most pronounced at rest, decreases with movement and is absent during sleep, increases with emotional stress and fatigue. The severity of the tremor decreases in the order of hands - shoulders - legs. The chewing muscles, tongue, forehead and eyelids may be involved, but the voice is not affected. As the disease progresses, the tremor may become less noticeable.

Rigidity without tremor often occurs. As rigidity progresses, movements become increasingly slow (bradykinesia), become more rare (hypokinesia), and are increasingly difficult to initiate (akinesia). Rigidity and hypokinesia contribute to the development of muscle pain and a feeling of weakness. The face becomes mask-like, the mouth is open, blinking is rare. At first, patients look depressed due to the "absent" facial expression, impoverishment and slowing of facial expressions. Speech becomes hypophonic with a characteristic monotonous dysarthria. Hypokinesia and impaired movement of distal muscles lead to micrographia (writing in very small letters) and complicates everyday self-care. During passive movements of the patient's limbs, the doctor feels rhythmic tremors (cogwheel-type rigidity).

The posture becomes hunched. Difficulty in starting to walk, turning and stopping is noted; the gait becomes shuffling, the steps are short, the arms are bent, brought to the waist and do not swing when walking. The steps accelerate and the patient can almost run, preventing a fall (mincing gait). The tendency to fall forward (propulsion) or backward (retropulsion) is associated with a shift in the center of gravity due to the loss of postural reflexes.

Dementia and depression are common. Orthostatic hypotension, constipation, or urinary problems may occur. Difficulty swallowing is common, which can lead to aspiration.

Patients cannot rapidly alternate between different movements. Sensation and strength are usually preserved. Reflexes are normal but may be difficult to elicit because of severe tremor and rigidity. Seborrheic dermatitis is common. Postencephalic parkinsonism may be accompanied by persistent deviation of the head and eyes (oculogyric crises), dystonia, autonomic instability, and personality changes.

Dementia in Parkinson's disease

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ICD-10 code

F02.3. Dementia in Parkinson's disease (G20).

It usually develops in 15-25% of patients with severe Parkinson's disease (degenerative-atrophic disease of the extrapyramidal system of the brain; tremor, muscle rigidity, hypokinesia). Signs of obvious cognitive deficit are detected in 14-53% of such patients. 

The clinical picture of dementia is not very specific. In addition to neurological obligatory symptoms of Parkinson's disease, personality changes are also considered, primarily determined by disturbances in the emotional-motivational sphere, decreased motivation, activity, emotional impoverishment, isolation, a tendency to depressive-hypochondriac forms of reaction). In differential diagnostics, it should be taken into account that similar clinical manifestations can occur in vascular (multi-infarct) dementia, in neoplasms of the brain.

Treatment for dementia in Parkinson's disease is specific.

The main antiparkinsonian therapy is carried out with L-DOPA drugs, which reduce dopamine deficiency. To them are added drugs with anticholinergic action (amantadine 200-400 mg/day for 2-4 months) and monoamine oxidase (MAO)-B blockers (selegiline 10 mg/day for a long time). Antiparkinsonian drugs with cholinolytic action are contraindicated in cases where dementia in patients with Parkinson's disease is caused by the addition of Alzheimer's disease. It is necessary to avoid the use of drugs that easily cause the development of neuroleptic parkinsonism. It is necessary to remember the high probability of developing psychotic side effects during treatment with antiparkinsonian drugs: confusion, psychomotor agitation with fear, hallucinatory disorders.

Expected treatment results:

• reduction of movement disorders;
• improving the quality of life of the patient and the people caring for him.

Rehabilitation measures for mild and moderate dementia include occupational therapy, psychotherapy, and cognitive training. Of particular importance, as with other forms of dementia, is working with family members and providing psychological support to people caring for the patient.

The course is determined primarily by the severity of neurological disorders. The prognosis worsens significantly when dementia is present.

Diagnosis of Parkinson's disease

The diagnosis is made on the basis of clinical data. Characteristic tremor at rest, bradykinesia or rigidity raise the question of Parkinson's disease. Bradykinesia in Parkinsonism should be differentiated from slowing of movements and spasticity in cases of damage to the corticospinal tracts. In the latter case, paresis (weakness or paralysis) develops, mainly in the distal muscles, and there are extensor plantar reflexes (Babinski's symptom). Spasticity in cases of damage to the corticospinal tract is combined with increased muscle tone and deep tendon reflexes; with passive stretching of the muscle, tone increases proportionally to the degree of tension, and then suddenly decreases (jackknife phenomenon).

The diagnosis of Parkinson's disease is confirmed by other characteristic symptoms (e.g., infrequent blinking, hypomimia, impaired postural reflexes, characteristic gait disturbances). Isolated tremor without other characteristic symptoms suggests an early stage of the disease or another diagnosis. In older people, decreased spontaneous movements or a gait with small steps (rheumatic) may be due to depression or dementia; such cases may be difficult to distinguish from Parkinson's disease.

The cause of Parkinsonism is determined based on the patient's medical history and brain imaging. Traumatic brain injury, stroke, hydrocephalus, drug and toxin exposure, and a history of other degenerative neurological diseases are important.

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Treatment of Parkinson's disease

Drugs for Parkinson's disease

Traditionally, the first drug is levodopa, but many believe that its early use accelerates the development of side effects and reduces sensitivity to the drug; they prefer, if possible, not to prescribe levodopa initially, but to use anticholinergic drugs, amantadine, or dopamine agonists.

Levodopa, a precursor of dopamine, crosses the blood-brain barrier and enters the basal ganglia, where it is decarboxylated into dopamine. Concomitant administration of the decarboxylase inhibitor carbidopa prevents catabolism of levodopa, allowing its dosage to be reduced, minimizing side effects.

Levodopa is most effective against bradykinesia and rigidity, although it also significantly reduces tremor. In mild cases, levodopa can return the patient to a virtually normal state, and transfer a bedridden patient to an outpatient regimen.

The main central side effects of levodopa include nightmares, orthostatic hypotension, drowsiness, dyskinesias, and hallucinations or delirium, especially in elderly people with dementia. Peripheral side effects include nausea, vomiting, hyperhidrosis, abdominal spasm, and tachycardia. The dose at which dyskinesias develop decreases as treatment continues. Sometimes the minimum dose that results in a reduction in parkinsonism symptoms also causes dyskinesias.

Carbidopa/levodopa in various ratios are available as 10/100, 25/100, 25/250, 25/100, 25/250, and extended-release 50/200 mg tablets. Treatment is initiated with a 25/100 mg tablet 3 times a day. The dose is increased every 4-7 days until the maximum beneficial effect is achieved or side effects occur. Side effects are minimized by gradually increasing the dose and administering the drug during or after meals (high-protein meals may impair absorption of levodopa). If peripheral side effects predominate, the carbidopa dose should be increased. Usually 400-1000 mg/day of levodopa is required in divided doses every 2-5 hours. Sometimes it is necessary to increase the daily dose to 2000 mg2.

Sometimes levodopa must be used to support motor functions despite the hallucinations or delirium it causes. Psychosis can sometimes be treated with quetiapine or clozapine orally. They hardly worsen the symptoms of parkinsonism, or do so to a lesser extent than other neuroleptics (eg, risperidone, olanzapine). Haloperidol should not be prescribed. The starting dose of quetiapine is 25 mg 1-2 times a day, it is increased by 25 mg every 1-3 days, if tolerated, up to 800 mg/day. The starting dose of clozapine is 12.5-50 mg 1 time per day, it is increased to 12.5-25 mg 2 times a day under weekly monitoring of clinical blood analysis for 6 months, then the analysis is taken once every 2 weeks.

1. A combination of levodopa with the decarboxylase inhibitor benserazide and catechol methyltransferase (KOMT) inhibitors is also used.
2. A similar tactic is used when using the combination drug benserazide/levodopa).

After 2-5 years of treatment with levodopa, motor fluctuations (the "on-off" phenomenon) occur in most cases, which may be a consequence of levodopa therapy or the result of the underlying disease. As a result, the period of improvement after each dose is shortened, and phases from severe akinesia to uncontrolled hyperactivity can be distinguished. Traditionally, when such fluctuations appear, levodopa is prescribed in minimally effective doses, and the intervals between doses are reduced to 1-2 hours. Alternatively, dopamine agonists are added, levodopa/carbidopa (200/50 mg) and selegiline are prescribed.

For monotherapy of the initial stages of Parkinsonism, amantadine 100 mg orally 1-3 times a day is effective in 50% of cases; it can be used further to increase the effect of levodopa. The drug increases dopaminergic activity and anticholinergic effects. After several months of monotherapy, amantadine often loses its effectiveness. Amantadine alleviates the course of Parkinson's disease when using neuroleptics. Side effects of amantadine include leg edema, symptomatic livedo, and confusion.

Dopamine agonists directly activate dopamine receptors in the basal ganglia. Oral bromocriptine 1.25-50 mg bid, pergolide 0.05 mg 1 time/day to 1.5 mg 3 times/day, ropinirole 0.25-8 mg 3 times/day, and pramipexole 0.125-1.5 mg 3 times/day are given. When given alone, they are rarely effective for more than a few years but may be effective at all stages of the disease. Early administration of these drugs in combination with low doses of levodopa slows the onset of dyskinesias and the on-off phenomenon, possibly because dopamine agonists stimulate dopamine receptors longer than levodopa. This type of stimulation is more physiological and preserves receptors better. Dopamine agonists are useful in late stages when the response to levodopa is diminished or an on-off phenomenon occurs. Side effects (eg, sedation, nausea, orthostatic hypotension, impaired consciousness, delirium, psychosis) limit the use of dopamine agonists. Reducing the dose of levodopa reduces the side effects of dopamine agonists. Rarely, pergolide provokes fibrosis (pleural, retroperitoneal, or cardiac valves).

Selegiline, a selective monoamine oxidase type B (MAOB) inhibitor, inhibits one of the two main enzymes that break down dopamine in the brain. Sometimes, in cases of mild on-off phenomenon, selegiline helps to prolong the effect of levodopa. When administered early as monotherapy, selegiline can delay the need for levodopa by about 1 year. By activating residual dopamine early in the disease or by reducing the oxidative metabolism of dopamine, selegiline slows disease progression. A dose of 5 mg orally twice a day does not cause a hypertensive crisis after eating cheeses containing tyramine, unlike nonselective MAO inhibitors that block isoenzymes A and B. Although selegiline itself is virtually devoid of side effects, it potentiates the side effects of levodopa (eg, dyskinesias, psychotic effects, nausea), dictating a reduction in its dose.

Rasagiline, a new MAOB inhibitor that is not metabolized to amphetamine, appears to be effective and well tolerated at any stage of the disease. Whether rasagiline has only a symptomatic or/and neuroprotective effect is not yet clear.

Anticholinergic drugs can be used as monotherapy in the early stage of the disease and later to support the action of levodopa. Among them are benztropine orally from 0.5 mg at night to 2 mg 3 times a day and trihexyphenidyl 2-5 mg orally 3 times a day. Antihistamines with anticholinergic effect are effective for the treatment of tremor (e.g. diphenhydramine 25-50 mg orally 2-4 times a day, orphenadrine 50 mg orally 1-4 times a day). Anticholinergic drugs (e.g. benztropine) can alleviate complaints of parkinsonism due to the use of neuroleptics. Tricyclic antidepressants with anticholinergic effect (e.g. amitriptyline 10-150 mg orally before bedtime) are effective when combined with levodopa. The dose of anticholinergic drugs is increased very slowly. Side effects of anticholinergic drugs, especially unpleasant in old age, include: dry mouth, urinary retention, constipation, visual disturbances; confusion, delirium and impaired thermoregulation due to decreased sweating.

Catechol-O-methyltransferase (COMT) inhibitors (eg, entacapone, tolcapone) inhibit dopamine breakdown and are therefore effective in combination with levodopa. Combinations of levodopa, carbidopa, and entacapone are possible. For each dose of levodopa, 200 mg of entacapone is prescribed once a day, but not more than 1600 mg/day (for example, if levodopa is used 5 times a day, 1 g of entacapone is prescribed once a day). Tolcapone is rarely used due to its toxic effect on the liver.

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Surgical treatment of Parkinson's disease

If the disease progresses despite modern therapy, the question of surgical treatment arises. The method of choice is high-frequency electrical stimulation of the subthalamic body. In case of dyskinesia induced by levodopa, stereotactic destruction of the posteroventral segment of the globus pallidus (pallidotomy) is performed. If bradykinesia, the "on-off" phenomenon and levodopa-induced dyskinesia are no more than 4 years old, then surgery significantly reduces the corresponding complaints. In case of pronounced tremor, stimulation of the medial ventral nucleus of the thalamus may be effective. Experiments are being conducted with a treatment that potentially increases the content of dopamine in the brain - transplantation of embryonic dopamine neurons.

Physical Treatments for Parkinson's Disease

The goal is to increase the daily activities of patients with Parkinson's disease as much as possible. A regular exercise program or physical therapy can help improve the physical condition of patients and teach them coping strategies. Constipation is common due to the disease, antiparkinsonian medications, and decreased activity, so a high-fiber diet should be followed. Dietary supplements (e.g., psyllium) and mild laxatives (e.g., bisacodyl 10-20 mg orally once a day) can help.