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Parkinson's Disease
Essentials
- Parkinson's disease usually begins at the age of 50-70.
- Hereditary form of the disease is rare.
- Diagnosis is based on essential symptoms and signs, especially on establishing slowness of movement (bradykinesia), resting tremor and muscle stiffness.
- Treatment is based on self-care, rehabilitation, pharmacotherapy and sometimes device-assisted therapies.
- The most important medications are levodopa, dopamine agonists and MAO-B inhibitors.
- Keep in mind drug-induced parkinsonism as an adverse effect of antipsychotic drugs and metoclopramide.
Aetiology
- Motor symptoms most typically appear at the age of 50-70 years.
- Age is a central risk factor. The disease is more common in men.
- The motor symptoms of the disease are caused by destruction of the neurones of the nigrostriatal neural pathway and consequent dimishing of dopamine in the striate body.
- The aetiology is unknown in most cases. It is estimated that 5-10% of the cases, especially in younger patients, are associated with monogenic mutations, but, in Finland, hereditary cases have been rarely found.
Symptoms
- Motor symptoms are usually unilateral in the beginning. Suspect other causes if the patient has symmetric bilateral symptoms without tremor.
- Most common motor symptoms
- Resting tremor in one hand is the most common initial symptom (video Tremor and Rigidity in Parkinson's Disease).
- The tremor is coarse and diminishes during voluntary movement.
- The jaw may tremble, whereas the head usually does not ("no-no" movement = Parkinson's disease is unlikely).
- Hypokinesia/bradykinesia
- Increase in muscle tone (rigidity; video Tremor and Rigidity in Parkinson's Disease)
- Rigidity may be felt either as constant (lead-pipe) or periodic (cogwheel) resistance.
- Other
- Associated movements are reduced, the steps become shorter and walking becomes slower. Unilateral reduction of associated movements is a common initial symptom.
- Forward leaning posture
- Balance problems
- Disturbances of autonomic nervous system (constipation, erectile dysfunction, orthostatic hypotension, urinary urgency, and difficulty in voiding)
- Drooling, difficulty in swallowing, soft voice, indistinct speech
- Greasy skin and seborrhoeic dermatitis on upper body and face
- Impaired sense of smell
- Behaviour disorder during REM sleep
- Depression, apathy and anxiety
- Parkinson's disease dementia in late phases of the disease; mild memory disturbances are more common than the actual memory disease
- Hallucinations and psychotic symptoms related to medication and late phases of the disease
- Expressions and blinking of the eyes are reduced (hypomimia).
- Writing becomes slower and handwriting is small (micrographia).
- All patients do not have all the symptoms.
Diagnosis
- Parkinson's disease is likely if the patient has two out of three major symptoms (resting tremor, hypokinesia, rigidity), especially as unilateral findings.
- The symptoms do not start rapidly within days or a week.
- Falling and dementia are not present in the initial phase.
- Incorrect diagnoses are caused especially by essential tremor Essential Tremor.
- Exclude diseases where symptoms or signs additional to those seen in Parkinson's disease are found (atypical parkinsonism, i.e. "Parkinson's Plus" diseases).
- Progressive supranuclear paralysis (restricted vertical movements of the eye)
- Multiple system atrophy (marked orthostatic hypotension or urinary incontinence already in the initial phase)
- Corticobasal syndrome (markedly unilateral limb rigidity, "alien hand" phenomenon and apraxia)
- Other, rare causes of secondary parkinsonism include hydrocephalus with normal pressure, intoxications (carbon monoxide, manganese, MPTP, methanol), as well as cerebrovascular disturbances, tumours and traumas.
- Consists of voluntary exercise, rehabilitation, drugs, and, as required, device-assisted therapies.
- Exercise and rehabilitation aim at preservation of functional capacity, balance and freedom of movement in the joints.
- A specialist in neurology should design the treatment, especially for younger patients (e.g. those still at work) in order to minimize the adverse effects of long-term treatment.
- Drug treatment is chosen individually, according to age and other illnesses.
- Total freedom from symptoms is not necessarily the aim.
- Patients should be informed of the beneficial effects of drugs, as well as of the most common adverse effects. They should also be encouraged to keep a diary of medication, meals and drug effects for 2-3 days before a follow-up visit.
- Patient education materials as well as adjustment training and rehabilitation courses are available. Find out about local availability.
- Dopaminergic cells transform levodopa into dopamine.
- Used concomitantly with a decarboxylase inhibitor (carbidopa, benserazide), which inhibits the metabolism of levodopa outside the central nervous system and thus diminishes peripheral adverse effects.
- Initial doses are usually low (e.g. 50 mg three times daily), and the dose is increased stepwise over a period of days-weeks, depending on the treatment response and adverse effects. In the initial phase, the daily dose is recommended not to exceed 400 mg.
- Absorption varies between individuals, and as the disease progresses higher doses are needed.
- The effect of the drug is scheduled to the waking state. In the early stages of the treatment (the first few years) the drug should be taken around 7 a.m., at noon, and at 5 p.m. (at about five-hour intervals) if the patient is awake from 7 a.m. to 10 p.m.
- Levodopa should be preferably taken about an hour before meal. If it is not possible, the drug may be taken about an hour after meal. There is no danger even if the drug is taken with meal, but its absorption may be slower or reduced.
- The bioavailability of depot preparations is approximately 70% compared to standard drugs, the plasma peak concentrations are lower, duration of effect is longer and onset of action is slower (within 2 hours). The effect of standard preparations begins in 45 minutes, unless they are chewed before swallowing. Water-soluble (dispersable) preparations have the most rapid onset of action, in about 15 minutes.
- The drug is usually effective for rigidity and mobility disorders and the adverse effects are tolerable in the beginning.
- Adverse effects
- Gastrointestinal (nausea, gastric pain, heartburn)
- Increased daytime tiredness
- Vertigo, sweating
- Confusion, hallucinations (with large doses)
- Cardiac arrhythmias (infrequent)
- Antipsychotics and metoclopramide decrease efficacy and iron preparations decrease absorption of the drug.
- Long-lasting treatment with levodopa causes dyskinesia or dystonia in many patients. Decreasing the dose diminishes these symptoms, but often the symptoms of Parkinson's disease are simultaneously aggravated. Another typical problem is the shortening of the duration of action of levodopa (wearing off). There are daily fluctuations in the condition of the patient.
- Younger patients are more susceptible to dyskinesia than older ones. As the expected treatment time in these patients is long, the aim in young patients (less than 60 years of age) is to start therapy primarily with drugs that do not cause motor fluctuations when used alone (e.g. MAO-B inhibitors and dopamine agonists).
- Act as MAO-B inhibitors and potentiate the action of levodopa. Selegiline is usually given 5-10 mg, rasagiline 1 mg and safinamide 50-100 mg in the morning.
- Concomitant use of MAO-A inhibitors is contraindicated (risk of hypertensive crisis).
- Selegiline may aggravate orthostatic hypotension and cause sleep disturbances.
- There is some evidence that MAO-B inhibitors may slow down the progression of the disease; results from studies are contradictory Selegeline for Early Parkinson's Disease.
- Reimbursement of safinamide may differ between countries.
COMT inhibitors (entacapone and opicapone)
- Entacapone and opicapone are a cathecol-O-methyltransferase (COMT) enzyme inhibitors. As levodopa is a substrate of the COMT enzyme, entacapone and opicapone slow the metabolization of levodopa in the body and thus prolong its effect.
- One entacapone dose (200 mg) is taken concomitantly with every levodopa dose usually as a combination product (levodopa + carbidopa + entacapone).
- One opicapone tablet (50 mg) is taken in the evenings at least one hour before levodopa or ar least one hour after it.
- Beneficial for patients suffering from fluctuation of the condition (wearing-off).
- May aggravate dopaminergic adverse effects, such as dyskinesia. In these cases the single dose of levodopa should be reduced.
- Entacapone may cause diarrhoea and abdominal pain and may colour the urine reddish.
- Stimulate dopamine receptors, i.e. act like dopamine.
- Pramipexole (tablet), ropinirole (tablet), rotigotine (transdermal patch) and apomorphine (subcutaneous injections) are the drugs in use.
- The patient must get used to the medication slowly.
- Medication is started at low doses and the dosage is gradually increased, usually during 4 to 8 weeks, up to the maintenance dose.
- Dopamine agonists are not as effective as levodopa but more effective than amantadine, anticholinergic drugs or MAO-B inhibitors.
- The advantage of these drugs compared with levodopa is their longer duration of action; the half-lifes of these drugs are several hours (levodopa 1 hour).
- Adverse effects are similar to those of levodopa, but more common.
- Especially nausea Dopamine Agonist Therapy in Early Parkinson's Disease and vomiting may occur in the initial phase of treatment. Hallucinations Dopamine Agonist Therapy in Early Parkinson's Disease, oedema of the lower extremities and orthostatism are the most common adverse effects in the long term. The elderly tolerate the drugs less well than younger patients.
- Falling asleep is a special adverse effect. The patient may fall asleep quite suddenly. This phenomenon has been described with all dopamine agonists.
- Patients using dopamine agonists may develop disturbances in impulse control, such as compulsive gambling, hypersexuality, compulsive shopping or excessive eating. Such disturbances have been reported in 14% of these patients.
- Apomorphine is an old dopamine-receptor agonist. An apomorphine self-injector (for s.c. administration) and an infusion device resembling an insulin pump (see below) are available.
- The effect of an apomorphine injection begins in minutes and lasts a short time (1-2 hours).
Anticholinergic drugs (biperiden)
- May be suitable for a young patient with tremor.
- Adverse effects are common.
- Treatment is initiated at a low dose, which is increased stepwise until an acceptable response is attained or adverse effects prevent further increase.
- Intravenous or intramuscular biperiden, available under special license, may have an effect in drug-induced dystonias.
- Adverse effects of anticholinergic drugs include impairment of memory even in patients with otherwise normal memory, visual disturbances, confusion (to be remembered if the patient has memory deficits), dryness of the mouth, constipation, urinary retention (to be remembered if the patient has prostatic hyperplasia).
Amantadine
- Originally developed for influenza A.
- The drug's beneficial effect on the symptoms of Parkinson's disease was discovered accidentally.
- Blocking of a glutamate receptor (N-methyl-D-aspartate, NMDA) is one mechanism of action.
- NMDA receptors are associated with dyskinesia, the reduction of which has become one of the indications of amantadine.
- The efficacy in parkinsonism is poor.
- The most common adverse effects include livedo reticularis, oedema of the lower extremities and hallucinations.
Device-assisted therapies
- Three device-assisted therapies are available.
- Deep brain stimulation (DBS)
- Levodopa infusion
- Apomorphine infusion
- Device-assisted therapies should be considered in cases where normal pharmacotherapy does not provide adequate relief of fluctuations or tremor.
- Most patients do not require device-assisted therapies.
- Deep brain stimulation administered via an electrode that is stereotactically implanted in the brain has mainly replaced the earlier local neuroablative procedure (thalamotomy, pallidotomy).
- Unilateral thalamotomy is still used, to some extent, in the treatment of patients with tremor to whom DBS is not applicable.
- The stimulation of the subthalamic nucleus may help especially in fluctuations of the condition (dyskinesias, wearing-off) Deep Brain Stimulation for Parkinson Disease.
- Thalamic stimulation is beneficial in the treatment of tremor Tremor.
- Levodopa infusion administered with the help of an external pump through a PEG tube into the small instestine balances fluctuations and is applicable also in elderly patients and in patients with cognitive problems.
- There are two levodopa infusion options: levodopa-carbidopa or levodopa-carbidopa-entacapone infusion.
- Apomorphine infusion is administered subcutaneously with the help of an external pump through an infusion cannula. It is especially applicable in patients who already are using an apomorphine injection pen.
- A referral for an assessment regarding device-assisted therapy is warranted if a patient who has had the disease for more than 5 years is not satisfied with his/her motor condition (quality of life, ability to perform in activities of daily living) and he/she is using levodopa at least 5 times a day.
- Dystonia
- Dystonia is a long-lasting and sometimes quite painful muscle contraction, which may occur both when the drug effect is present (on-dystonia) and at other times (off-dystonia).
- A common type is early morning off-dystonia that appears in lower extremities.
- Levodopa may be beneficial; however, the intensity of dystonia may also increase with the rise and fall of plasma drug concentration.
- An anticholinergic drug may also be beneficial in the treatment of dystonia.
- Dystonia occurring in the morning or at nights can be managed with dopamine-receptor agonists, as these drugs have a long duration of action, as well as with diazepam (5 mg) taken at bedtime or with levodopa as a depot preparation in the evening.
- In the morning or at night, the most rapid levodopa effect is achieved with a dispersible (water-soluble) preparation form.
- Confusion and hallucinations associated with antiparkinsonian medications
- Frequently a severe problem.
- In long-enduring disease and in the elderly, confusion correlates in most cases with the decline in cognitive function.
- Classic antipsychotic drugs cannot be used, as these drugs block dopamine receptors and aggravate the symptoms of Parkinson's disease.
- Second-generation antipsychotics, such as quetiapine, can be considered if the drug is started with low doses (sedation may prevent use). A suitable initial dose is 12.5-25 mg evenings.
- Acetylcholinesterase inhibitors (AChEI), such as rivastigmine, may be beneficial in the treatment of hallucinations. These drugs may, however, increase tremor.
- Depression
- Parkinson's disease dementia
- Treatment of end-stage akinetic patient
- The effect of levodopa has diminished but other drugs are of no use either.