Parkinson’s disease
Parkinson’s disease is a slowly progressive degenerative disorder characterized by resting tremor, rigidity (stiffness), slow and decreased movement (bradykinesia) and gait and / or postural instability. The diagnosis is made clinically. The treatment aims dopaminergic function in the brain with levodopa plus carbidopa and / or other drugs restored (for example, as dopamine agonists, MAO Type B [MAO-B] inhibitors, amantadine). In refractory, disabling symptoms in patients without dementia stereotactic deep brain stimulation or lesional surgery and levodopa and apomorphine pump can help.
Parkinson’s disease (MP) affects about
Parkinson’s disease is a slowly progressive degenerative disorder characterized by resting tremor, rigidity (stiffness), slow and decreased movement (bradykinesia) and gait and / or postural instability. The diagnosis is made clinically. The treatment aims dopaminergic function in the brain with levodopa plus carbidopa and / or other drugs restored (for example, as dopamine agonists, MAO Type B [MAO-B] inhibitors, amantadine). In refractory, disabling symptoms in patients without dementia stereotactic deep brain stimulation or lesional surgery and levodopa and apomorphine pump can help. Parkinson’s disease (MP) affects about 0.4% of people> 40 years 1% of people ? 65 years 10% of people ? 80 years, the average age of onset is about 57 years. PD is idiopathic in general. Rarely starts MP during childhood or adolescence (juvenile parkinsonism). The appearance in the ages of 21 and 40 years is sometimes called young or early-onset form of MP. Genetic causes are likely in the juvenile and early-onset form; these forms may be different from the later onset MP because they progress slowly and are very sensitive to dopaminergic treatment and because the main disability of non-motor symptoms such as depression, anxiety and pain comes. Secondary parkinsonism is a dysfunction of the brain that is characterized by dopaminergic blockade of the basal ganglia and MP is similar, but has a cause other than MP (z. B. medications, cerebrovascular disease, trauma, postencephalitic changes). Atypical parkinsonism refers to a group of neurodegenerative diseases that have some characteristics similar to MP, but a number of other clinical features and a different pathology have (z. B. neurodegenerative diseases such as multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, corticobasal degeneration). Pathophysiology synuclein is a protein in neurons and glial cells, the aggregate into insoluble fibrils and Lewy bodies can be formed. The pathological hallmark of PD is synuclein-containing Lewy bodies in the nigrostriatal system, however synuclein can accumulate in many other parts of the nervous system, incl. The dorsal motor nucleus of the vagus, the nucleus basalis of Meynert, hypothalamus, neocortex, olfactory bulb, sympathetic ganglia and myenteric plexus of the gastrointestinal tract. Lewy bodies appear in a time sequence, and many experts believe that MP is a relatively late development in a systemic Synukleinopathie. Other synucleinopathies (interference from Synukleinablagerung) are dementia with Lewy bodies and multiple system atrophy. MP may share common features with other synucleinopathies have as autonomic dysfunction and dementia. MD rarely comes without Lewy bodies before (z. B. in a mold due to a mutation in site 2 gene). In MP pigmented neurons degenerate in the substantia nigra, the locus coeruleus and other dopaminergic neuronal populations in the brain stem. The loss of substantia nigra neurons results in the depletion of dopamine in the dorsal putamen (part of the basal ganglia) and causes many of the motor manifestations of MP. Etiology is a genetic predisposition, in at least some cases of PD, probably. About 10% of patients have a family history of MP. Several abnormal genes have been identified. For some genes the inheritance is autosomal dominant, for other autosomal recessive trait. In genetically related forms, age is rather younger at the start, but the course is usually benign and the later onset, probably not genetic MP. Symptoms and signs in most patients begin PD symptoms gradually. A resting tremor of a hand is often the first symptom. The tremor is characterized as follows: Slowly and grobschlägig maximum at rest, decreasing with movement and absent during sleep, the amplitude is increased by emotional tension or fatigue Often, the inclusion of the wrist and fingers, sometimes the thumb is moved towards the index finger (pill turning), as if the person turns a pill in your hand or with a small object handled usually the hands or feet are usually asymmetrical, affected first. Jaw and tongue can be affected, but not the voice. With the progression of the disease tremor is increasingly blurred. Stiffness regardless of the tremor develops in many patients. The examiner moves a rigid joint, semi-rhythmic contractions may occur because of varying intensity of the rigors and a grid-like effect producing (gear phenomenon). Slow movements (bradykinesia) are typical. The movements are also concerning. The amplitude decreased (hypokinesia) and difficult to initiate (akinesia). Rigor and hypokinesia may contribute to muscle pain and a feeling of fatigue. The face is mask-like (hypomimisch), with open mouth and reduced blinking. Excessive salivation (sialorrhea) may contribute to disability. The language is hypophon, with a characteristic monotone, sometimes stuttering dysarthria. The hypokinesia and the impaired control of distal muscles cause micrograph (writing in very small letters) and make daily activities more difficult. Without warning, a voluntary movement, incl. Go to suddenly stop (so-called. Freezing of gait). Attitude instabilities can develop and lead to falls that occur later in the course of MD. Patients find it difficult to start walking, they turn around and pause. You shuffle, take short steps, holding her arms around the waist bent and swinging her arms with each step little or not at all. The steps may be accelerated unintentionally, during the stride is increasingly shortened; this gait disorder, called. festination is often a precursor to freeze the transfer. The tendency to fall upon displacement of the center of gravity forward or backward (Pro or retropulsion), is the consequence of the failure of the housing and righting reflexes. The posture is stooped. Dementia develops late about one third of patients, usually in PD. Early predictors of their development are visuospatial impairments (eg. As getting lost while driving) and reduced flow of speech. Sleep disorders are common. Insomnia can result from nocturia or the inability to turn over in bed. It can develop a rapid-eye-movement (REM) sleep behavior disorder; in this disorder violent outbursts of physical activity during REM sleep occur because the paralysis is missing, which is normally during REM sleep. Lack of sleep can increase depression and cognitive impairment, as well as contribute to excessive daytime sleepiness. Recently, it has been shown in studies that the rapid eye movement sleep behavior disorder is a marker for synucleinopathies, indicating a higher risk of developing dementia with Lewy bodies or dementia in Parkinson’s disease. Neurological symptoms unrelated to Parkinsonismusentstehen often because the Synukleinopathie occurs in other areas of central, peripheral and autonomic nervous system. Examples include: Nearly universal sympathetic denervation of the heart, which contributes to orthostatic hypotension motility disorders of the esophagus leading to dysphagia and an increased risk of aspiration contribute motility disturbances in the lower abdomen that contribute to constipation urinary retention and / or urination, possibly leading to incontinence leads (often) anosmia (often) in some patients some of these symptoms before the motor symptoms of MP occur. A seborrheic dermatitis also often occurs. Diagnosis vorranging clinical assessment based on motor symptoms, the MP-diagnosis is made clinically. MP is suspected in patients with a characteristic unilateral resting tremor, decreased movement or rigidity. The tremor disappears (or weaker) during finger-to-nose coordination tests. During the neurological examination, the patient can not perform well or quickly changing rapidly successive movements. Sensitivity and strength are usually normal. The reflexes are normal, but can be hard to trigger due to a significant tremor or rigors. Slow and decreased movement due to MP must be distinguished from reduced movements and spasticity due to lesions of the corticospinal pathways. Unlike MP cause lesions of the corticospinal tract paralysis (weakness or paralysis), preferably in the distal muscles against gravity hyperreflexia extensor plantar reflex (Babinski sign) Spasticity that muscle tone is proportional to the speed and the extent of passive stretching of the muscle increases until the resistance suddenly subsides (folding knife phenomenon). The diagnosis MP is supported by the presence of other symptoms such as rare blinking, lack of mimic expression, impaired postural reflexes and characteristic gait abnormalities. In older people, other possible causes reduced spontaneous movements or small steps gangs like severe depression, hypothyroidism or the use of antipsychotics or certain antiemetics must be ruled out before MP can be diagnosed. To distinguish MP of secondary or atypical parkinsonism, clinicians often test the response to levodopa. A large, sustained response confirms strong one MP. Little or no response to levodopa in doses of at least 1200 mg / day speaks for another form of parkinsonism. Causes of secondary or atypical parkinsonism can be identified by a thorough medical history, incl. Labor, drug / drug and family history The evaluation of neurological deficits that are characteristic of other disorders as MP Neuroimaging when patients have atypical features (eg . B. early falls, early cognitive impairment, ideomotor apraxia [inability to imitate hand gestures], hyperreflexia) treatment carbidopa / levodopa (mainstay of treatment) amantadine, MAO type B (MAO-B) inhibitor, or, in a few patients anticholinergics dopamine agonists catechol-O-methyltransferase (COMT) inhibitor, used always together with levodopa, especially when the response Levodopa wears surgical measures if medications do not control symptoms adequately, or at nichttolerablen side effects training and adaptation measures Many oral medications are often used to alleviate the symptoms of MP used (see table: oral anti-Parkinson drugs frequently used). Levodopa is the most effective treatment. However, in advanced MP, sometimes soon after diagnosis, the response may decrease to levodopa, resulting in fluctuations in motor Symptomne and dyskinesia (levodopa). To shorten the treatment period for levodopa and thus minimize these effects, physicians may consider younger patients with mild obstruction with MAO-B inhibitors (selegiline, rasagiline) dopamine agonists (for. Example, pramipexole, ropinirole, rotigotine) amantadine (which is also the best option when attempting to reduce the high of dyskinesias) however, if these drugs control the symptoms is not enough, the doctor should immediately levodopa because it can greatly improve the quality of life in general. Notes speak now that levodopa is ineffective due to disease progression and not because of the cumulative exposure to levodopa, which had been previously thought, so that the early use of levodopa probably not accelerate the ineffectiveness of the drug. The doses are often reduced in the elderly. Drugs that cause symptoms or worsen, particularly antipsychotics, are avoided. Levodopa Levodopa, the metabolic precursor of dopamine, passes through the blood-brain barrier in the basal ganglia, where it is decarboxylated to dopamine. The concomitant use of the peripheral decarboxylase inhibitor carbidopa prevents levodopa is decarboxylated outside the brain (peripheral) to dopamine, thereby increasing the dose of levodopa would be reduced, which is required to achieve therapeutic concentrations in the brain, and minimizes the adverse effects by dopamine in peripheral blood circulation. Levodopa works best on bradykinesia and on the rigor, but it often also significantly reduces the tremor. are common short-term adverse effects of levodopa nausea include vomiting dizziness common unerwünsche long-term effects mental and psychiatric disorders (eg. as delirium with confusion, paranoia, visual hallucinations, Punding [complex, repetitive, stereotyped behaviors]) Motor dysfunction (z. B. dyskinesias, motor fluctuations) hallucinations and paranoia are most common in the elderly and in patients with cognitive impairment or dementia. The dose that induces dyskinesia increases, tends to decrease with the progression of the disease. Over time, the dose needed for therapeutic benefit, and the dose which causes the dyskinesias converge. The dose of carbidopa / levodopa is increased as tolerated every 4-7 d until the maximum benefit is achieved or adverse effects occur. The risk of adverse effects can be minimized by starting with a low dose, about half of a 25/100-mg tablet of carbidopa / levodopa 3 times / day, or 4 times / day (12.5 / 50 mg 3 times / day, or 4 times / day), and the slow increase to about 1, 2 or 3 25/100-mg tablet 4 times / day. Preferably levodopa should not be given with meals because protein can reduce the absorption of levodopa. If peripheral adverse effects of levodopa predominate (eg., Nausea, vomiting, drowsiness after waking up), increasing the amount of carbidopa can help. Carbidopa doses up to 150 mg are safe and do not reduce the effectiveness of levodopa. Most patients with MP need 400-1200 mg / day of levodopa in divided doses every 2-5 hours, but some patients with malabsorption require up to 3000 mg / day. A soluble form of oral carbidopa / levodopa immediate release can be taken without water; This form is for patients who have difficulty swallowing. The dosages are the same as NONDISSOLVING carbidopa / levodopa immediate release. It is a recipe for the controlled release carbidopa / levodopa available; However, this is generally used only to treat nocturnal symptoms, because – if they are taken with food – it can be absorbed erratically, and it is in the stomach longer available as immediate-release forms. Sometimes levodopa must be used to maintain motor function despite levodopa-induced hallucinations or delirium. A psychosis can sometimes be treated with oral quetiapine or clozapine; these drugs aggravate not Parkinson’s symptoms unlike other antipsychotics (eg. as risperidone, olanzapine, all the conventional antipsychotics). Quetiapine can be started and in 25 mg increments every 1-3 with 25 mg at night. Day to 400 mg / day or 200 mg at night increased 2 times / day. Although clozapine is most effective, the use is limited because agranulocytosis (estimated to occur in 1% of patients), constitutes a risk. Is clozapine used, the dose is between 12.5 to 50 mg once daily and 25 mg 2 times / day. A blood count is prepared every week for 6 months and every 2 weeks for 6 months and then every 4 weeks. However, the frequency as a function of the number of leukocytes may vary. Recent evidence suggests that Pimavanserin is effective in psychotic symptoms and not aggravate Parkinson’s symptoms; A drug surveillance does not appear necessary. Pending further confirmation of the efficacy and safety Pimavanserin, the drug of choice for psychosis in PD After 2-5 years of treatment, most patients experience fluctuations effect of levodopa, and the control of symptoms may fluctuate unpredictably between effective and ineffective (on-off phenomenon), whereas the response to levodopa wear out begins. Symptoms can before the next scheduled dose occur (so-called. Off-effects). Dyskinesias and off-effects arise from a combination of the pharmacokinetics of levodopa, in particular its short half-life (because it is an oral drug) and the disease progression. Dyskinesias resulted primarily from the Krankheitsprogession and are not, as previously thought, directly related to the cumulative exposure to levodopa. The course of the disease is connected with a pulsating oral administration of levodopa, which sensitizes the glutamatergic receptors and altered, especially the NMDA (N-methyl-t-aspartate) receptors. Finally, the time span of the motor improvement after each dose of levodopa becomes shorter, and drug-induced dyskinesias result in oscillation between akinesia and dyskinesia. Traditionally, such variations at the lowest possible levodopa doses and short intervals of 1-2 h are handled between the individual Levodopagaben, which is highly impractical. Alternative methods to shorten the (akinetic) off times include the additional use of dopamine agonists and COMT and / or MAO inhibitors; Amantadine dominated dyskinesia reliable. A formulation of levodopa / carbidopa intestinal gel (available in Europe) may be introduced by means of a pump connected to a feeding tube in the proximal small intestine. This formulation is being investigated as a treatment for patients with severe motor fluctuations and dyskinesias, which can not be alleviated by drugs and who do not qualify for deep brain stimulation in question. This formulation seems to significantly reduce and the quality of life erhöhen.Amantadin Amantadine is used most for the following off-hours: alleviating dyskinesia as a result of levodopa Reduced tremors amantadine is effective as monotherapy in early, mild Parkinson’s forms and can later on augmentation of Levodopawirkung be used. It may increase the dopaminergic activity and anticholinergic effects or both. Amantadine is also an NMDA receptor antagonist and can thus help to slow the progression of MP and dyskinesias. When used as monotherapy amantadine frequently loses after a few months, his Wirksamkeit.Dopaminagonisten enable These drugs directly dopamine receptors in the basal ganglia. These include: Pramipexole (0.75 to 4.5 mg / day po) ropinirole (3 to 6 mg / day po up to 24 mg / day) rotigotine (transdermal given) apomorphine (given by injection) bromocriptine may indeed even in some countries are used, but in North America the use is largely limited to the treatment of pituitary adenomas, as the risk for heart valve and pleural fibrosis is increased. Pergolide, a senior, derived from ergot dopamine agonist, was taken off the market because of the increased risk of heart valve fibrosis. Oral dopamine agonists may be used as monotherapy, but they are rarely more than a few years in this use effectively. The early use of these drugs in the treatment, along with low doses of levodopa can be useful in patients with a high risk of dyskinesia and on-off effects (eg. As in patients <60 years). However, dopamine agonists can be in all stages of the disease useful as adjunctive therapy in the later stages. Adverse effects may limit the use of oral dopamine agonists. In 1-2% of patients, these drugs can cause compulsive gambling, excessive shopping behavior, hypersexuality or overeating, which requires a dose reduction or discontinuation of the causative drug and possibly avoiding the whole class of drugs. Rotigotine administered once daily transdermal, provides a more continuous dopaminergic stimulation as drugs that are administered by other routes. It was kürzllich reintroduced in the US after technical problems with the patch technology were dissolved. is started once a day with a dose of 2 mg, which is usually increased to 6 mg once daily. Outside the US, higher doses may be recommended. Apomorphine is an injectable dopamine agonist for use as rescue therapy when the off-effects occur more frequently and are more severe. The onset of action is rapid (5-10 min), with its duration short (60-90 min). Apomorphine 2-6 mg s.c. can be up to 5 times / day be administered as needed. First, a 2 mg dose is given test for verification of orthostatic hypotension. Before treatment and 20, 40 and 60 min after the blood pressure in supine and standing is checked. Other adverse effects similar to those of other dopamine agonists. By 3 days prior to apomorphine administered with 300 mg po trimethobenzamide started 3 times / day and this is maintained for the first 2 months of treatment, the nausea can be prevented. Apomorphine administered by subcutaneous pump is available in some countries; it can be used instead of a Levodopa-pump in patients who have advanced PD and are not candidates for functional surgery sind.Selektive MAO-B inhibitors These drugs selegiline and rasagiline. Selegiline inhibits one of the two essential enzymes that degrade dopamine in the brain, and thus prolongs the effect of each levodopa administration. In some patients with mild off-effects selegiline helps to extend the effectiveness of levodopa. With initially employed as monotherapy selegiline to mild symptoms can be controlled; characterized the use of levodopa can be delayed by about one year. A dose of 5 mg p.o. 2 times / day does not cause hypertensive crisis (because of the amphetamine-like metabolites of the drug) as they triggered sometimes in patients who are taking a non-selective MAO inhibitors by the consumption of tyramine in foods (eg. As some cheeses) becomes. Although selegiline as has virtually no side effects, it may increase levodopa-induced dyskinesia, mental and psychiatric side effects and nausea, so a dose reduction of levodopa may be needed. Selegiline is also available in a formulation for buccal absorption (Zydis selegiline). Rasagiline inhibit the same enzymes, such as selegiline. It is effective and well tolerated in early and late stages of the disease; Rasagiline 1-2 mg p.o. once a day similar to that of selegiline. Unlike selegiline, it has no amphetamine metabolites, so is the risk of hypertensive crisis if patients consume tyramine, theoretically with rasagiline niedriger.Anticholinergika anticholinergics can later be used to support the levodopa therapy as monotherapy in early disease stages or. They are most effective in tremor. The doses are increased very slowly. Adverse effects may include cognitive impairment, and dry mouth, which are particularly problematic for older people and the main problem may, if the use of these drugs. Thus, anticholinergic drugs are generally only used in young patients with MP with predominantly tremor or with some dystonic components. They rarely be used in elderly patients without cognitive impairment or psychiatric conditions for supportive treatment. anticholinergic drugs commonly used are benztropine and trihexyphenidyl. Antihistamines with anticholinergic effects (z. B. Iphenhydramin 25-50 mg p.o. 2 to 4 times / day, p.o. orphenadrine 50 mg 1 to 4 times / day) are sometimes effective in the treatment of tremor. Can (10-150 mg po at bedtime z. B. amitriptyline) anticholinergic tricyclic antidepressants when used in depression, useful as co-medication to levodopa sein.Catechol- O -methyltransferase (COMT) inhibitors, these drugs (eg. B . entacapone, tolcapone) inhibit the breakdown of levodopa and dopamine and a useful co-medication to levodopa therefore seem to represent. They are often used in patients who have taken levodopa over a long period, when the response to levodopa at the end of the dosing interval gradually subsides (known as wearing-off effect). Entacapone can be used with levodopa and carbidopa in combination. For each dose of levodopa, entacapone 200 mg to a maximum of 200 mg of 8 times / day are given. Tolcapone is a potent COMT inhibitor, because it can cross the blood-brain barrier, but it is not used as often as it has been rare reports of liver toxicity. It is a suitable option if entacapone does not control the off-effects sufficient. The tolcapone dose is gradually increased from 100 to 200 mg 3 times / day. Liver enzymes should be monitored regularly. Tolcapone should be discontinued if ALT (GPT) - or AST (GOT) values ??increase to twice the upper limit of normal or above or if symptoms and discomfort that speak for liver damage. oral anti-Parkinson drugs commonly used drug dose Average daily dose * and maximum dose, if applicable Main adverse effects of dopamine precursor Carbidopa / Levodopa 10/100, 25/100 or 25/250 mg (immediate release or soluble) 1 / 2-1 Tbl. with 25/100 mg 3 or 4 times / day with 1-3 Tbl 25/100 mg 4 times daily central. drowsiness, confusion, orthostatic hypotension, psychotic disorders, nightmares, Dyskinesi e Peripheral: nausea, anorexia, flushing, abdominal cramps, palpitations A sudden withdrawal: Neuroleptic malignant syndrome carbidopa / levodopa 25/100 or 50/200 mg (controlled release, recommended [not during the day] only for nocturnal symptoms) 1 tablet with 25 /. 100 mg at bedtime 2 Tbl. with 50/200 mg at bedtime antiviral agent amantadine 100 mg once daily 100-200 mg of 2 times / day confusion, urinary retention, leg edema, increased intraocular pressure, livedo reticularis rare, discontinuation or reduction of D osis: Neuroleptic malignant syndrome dopamine agonists pramipexole 0.125 mg three times / day 0.5-1 mg 3 times / day Maximum dose: Can be dosed once daily nausea, vomiting, sleepiness: 4.5 mg / day extended-release formulation , orthostatic hypotension, dyskinesia, confusion, hallucinations, delirium, psychosis, gambling, compulsive behavior upon sudden withdrawal: withdrawal syndrome or neuroleptic malignant syndrome ropinirole 0.25 mg 3 times / day 3-4 mg 3 times / day Maximum dose: 24 mg/Tag Extende d-Release-Formulierung: Kann einmal täglich dosiert werden Anticholinergika* Benztropin 0,5 mg nachts 1 mg 2-mal/Tag bis 2 mg 3-mal/Tag Mundtrockenheit, Harnverhalt, Obstipation, verschwommenes Sehen Besonders bei älterenPatienten: Verwirrtheit, Delir, gestörte Thermoregulation wegen verminderter Schweißproduktion Trihexyphenidyl 1 mg 3-mal/Tag 25 mg 3-mal/Tag Monoaminoxidase-Typ-B(MAO-B)-Hemmer Rasagilin 0,5 mg einmal täglich 12 mg einmal täglich Übelkeit, Schlaflosigkeit, Somnolenz, Ödeme Selegilin 5 mg einmal täglich 5 mg 2-mal/Tag Mögliche Potenzierung von Übelkeit, Schlaflosigkeit, Verwirrtheit und Dyskinesien bei Einnahme zusammen mit Levodopa C