neurologic disorders
Parkinson Disease
Treatment of Parkinson Disease
Carbidopa/levodopa(mainstay of treatment) Amantadine, MAO type B (MAO-B) inhibitors, or, in few patients, anticholinergic drugs Dopamineagonists CatecholO-methyltransferase (COMT) inhibitors, always used withlevodopa, particularly when response tolevodopais wearing off Surgery if drugs do not sufficiently control symptoms or have intolerable adverse effects Exercise and adaptive measures Many oral drugs are commonly used to relieve symptoms of Parkinson disease (see table Some Commonly Used Oral Antiparkinsonian Drugs ). can wear off, causing fluctuations in motor symptoms and dyskinesias (see Levodopa ). To reduce the time MAO-B inhibitors (selegiline,rasagiline) Dopamineagonists (eg,pramipexole,ropinirole,rotigotine) Amantadine(which is also the best option when trying to decrease peak-dose dyskinesias) However, if these drugs do not sufficiently control symptoms, clinicians should promptly initiatelevodopabecause it can usually greatly improve quality of life. Evidence now suggests thatlevodopabecomes ineffective because of disease progression rather than cumulative exposure tolevodopa, as was previously believed, so early use oflevodopaprobably does not hasten the drug's ineffectiveness. Doses are often reduced in older patients. Drugs that cause or worsen symptoms, particularly antipsychotics, are avoided. Levodopa, the metabolic precursor ofdopamine, crosses the blood-brain barrier into the basal ganglia, where it is decarboxylated to formdopamine. Coadministration of the peripheral decarboxylase inhibitorcarbidopapreventslevodopafrom being decarboxylated intodopamineoutside the brain (peripherally), thus lowering thelevodopadosage required to produce therapeutic levels in the brain and minimizing adverse effects due todopaminein the peripheral circulation. Levodopais most effective at relieving bradykinesia and rigidity and often substantially reduces tremor. Common short-term adverse effectsoflevodopaare Nausea Vomiting Light-headedness Common long-term adverse effectsinclude Mental and psychiatric abnormalities (eg, delirium with confusion, paranoia, visual hallucinations, punding [complex, repetitive, stereotyped behaviors]) Motor dysfunction (eg, dyskinesias, motor fluctuations) Hallucinations and paranoia occur most often in older patients and in patients who have cognitive impairment or dementia. The dose that causes dyskinesias tends to decrease as the disease progresses. Over time, the dose that is needed for therapeutic benefit and the one that causes dyskinesia converge. Dosage ofcarbidopa/levodopais increased every 4 to 7 days as tolerated until maximum benefit is reached or adverse effects develop. The risk of adverse effects may be minimized by starting at a low dose, such as half of a 25/100 mg ofcarbidopa/levodopatablet 3 or 4 times a day (12.5/50 mg 3 or 4 times a day), and increasing the dosage slowly to about one 25/100-mg tablets up to 4 times a day. Based on the patient's tolerance and response, clinicians can increase the dosage every week up to 2 or 3 tablets 4 times a day. In less common circumstances, the dose oflevodopamay be increased up to 3 tablets 5 times a day. Most patients with Parkinson disease require 400 to 1200 mg a day oflevodopain divided doses every 2 to 5 hours, but very rarely, some patients with malabsorption require up to 3000 mg a day. Preferably,levodopashould not be given with food because protein can reduce absorption oflevodopa. Four to 5 doses oflevodopaa day are recommended to decrease the effect of fluctuating plasma levels oflevodopaon different basal ganglia, which, can cause motor fluctuations and dyskinesias. If peripheral adverse effects oflevodopa(eg, nausea, vomiting, postural light-headedness) predominate, increasing the amount ofcarbidopamay help.Carbidopadoses up to 150 mg are safe and do not decrease the efficacy oflevodopa. Domperidone can be used to treat the adverse effects oflevodopa(and other antiparkinsonian drugs). It blocks peripheraldopaminereceptors and does not cross the blood-brain barrier to affect the brain. By decreasing the decarboxylation oflevodopatodopamine, domperidone lessens the peripheral adverse effects oflevodopa, thereby decreasing nausea, vomiting, and orthostatic hypotension. The recommended dosages are Immediate-release: 10 mg orally 3 times a day, increased up to 20 mg 3 times a day if needed Sustained-release: 30 to 60 mg once in the morning (this dose may be enough to controllevodopa's peripheral adverse effects) Domperidone is not routinely available in the US. A dissolvable immediate-release oral form ofcarbidopa/levodopacan be taken without water; this form is useful for patients who have difficulty swallowing. Doses are the same as for nondissolvable immediate-releasecarbidopa/levodopa. A controlled-release preparation ofcarbidopa/levodopais available; however, it is usually used only to treat nighttime symptoms because when taken with food, it can be absorbed erratically and it is present longer in the stomach than immediate-release forms. New forms oflevodopadelivery are available or being developed, but none has yet been shown to be superior to immediate-releasecarbidopa/levodopa25/100 mg. Occasionally,levodopamust be used to maintain motor function despitelevodopa-induced hallucinations or delirium. In such cases, hallucinations and delirium can be treated with drugs. Psychosishas been treated with oralquetiapineorclozapine; these drugs, unlike other antipsychotics (eg,risperidone,olanzapine, all typical psychotics), do not aggravate parkinsonian symptoms.Quetiapinecan be started at 25 mg at night and increased in 25-mg increments every 1 to 3 days up to 400 mg at night or 200 2 times a day. Althoughclozapineis most effective, its use is limited because agranulocytosis is a risk (estimated to occur in 1% of patients). Whenclozapineis used, the dose is 12.5 to 50 mg once a day to 12.5 to 25 mg 2 times a day. A complete blood count (CBC) is done weekly for 6 months and every 2 weeks for another 6 months and then every 4 week thereafter. However, the frequency may vary depending on the white blood cell (WBC) count. Recent evidence suggests thatpimavanserinis efficacious for psychotic symptoms and does not aggravate parkinsonian symptoms; also drug monitoring does not appear necessary. Pending further confirmation of efficacy and safety,pimavanserinmay become the drug of choice for psychosis in Parkinson disease. After 2 to 5 years of treatment, most patients experience fluctuations in their response tolevodopa, and symptom control may fluctuate unpredictably between effective and ineffective (on-off fluctuations), as response tolevodopastarts to wear off. Symptoms may occur before the next scheduled dose (called off effects). The dyskinesias and off effects result from a combination of the pharmacokinetic properties oflevodopa(particularly its short half-life as an oral drug), and disease progression. Early in Parkinson disease, there are enough surviving neurons to buffer any oversaturation of dopaminergic receptors in the substantia nigra. As a result, dyskinesias are less likely to occur, andlevodopa's therapeutic effect lasts longer because of the reuptake of excessivelevodopaand its reutilization. As dopaminergic neurons are further depleted, each dose oflevodopasaturates more and moredopaminereceptors, resulting in dyskinesias and motor fluctuations because the delivery oflevodopato the substantia nigra becomes dependent on the plasma half life oflevodopa(1.5 to 2 hours). However, dyskinesias result mainly from disease progression and are not directly related to cumulative exposure tolevodopa, as previously believed. Disease progression is associated with pulsatile administration of orallevodopa, which sensitizes and changes glutamatergic receptors, especially NMDA (N-methyl-d-aspartate) receptors. Eventually, the period of improvement after each dose shortens, and drug-induced dyskinesias result in swings from akinesia to dyskinesias. Traditionally, such swings are managed by keeping thelevodopadose as low as possible and using dosing intervals as short as every 1 to 2 hours, which are impractical. Alternative methods to decrease the off (akinetic) times include adjunctive use ofdopamineagonists, as well as COMT and/or MAO inhibitors;amantadinemay help manage dyskinesias. A formulation oflevodopa/carbidopaintestinal gel (available in Europe) can be given using a pump connected to a feeding tube inserted in the proximal small bowel. This formulation is being studied as treatment for patients who have severe motor fluctuations and/or dyskinesias that cannot be relieved by drugs and who are not candidates for deep brain stimulation. This formulation appears to greatly reduce the off times and increase quality of life. Amantadineis most often used to do the following: Ameliorate dyskinesias secondary tolevodopa Lessen tremors Amantadineis useful as monotherapy for early, mild parkinsonism and later can be used to augmentlevodopa’s effects. It may augment dopaminergic activity, anticholinergic effects, or both.Amantadineis also an NMDA-receptor antagonist and thus may help slow the progression of Parkinson disease and dyskinesias. If used as monotherapy,amantadineoften loses its effectiveness after several months. These drugs directly activatedopaminereceptors in the basal ganglia. They include Pramipexole(0.75 to 4.5 mg orally [total daily dose]) Ropinirole(3 to 6 mg orally up to 24 mg [total daily dose]) Rotigotine(given transdermally 2 to 8 mg [total daily dose]) Apomorphine(given by injection 2 to 30 mg [total daily dose]) Apomorphineis used to treat acute intermittent bradykinesia; dosage is 2 to 30 mg subcutaneously as needed, starting at 2 mg once a day, then increased gradually up to a maximum of 6 mg 5 times a day). Bromocriptinemay still be used in some countries, but in North America, its use is largely limited to treatment of pituitary adenomas because it increases the risk of cardiac valve fibrosis and pleural fibrosis. Pergolide, an older ergot-deriveddopamineagonist, was taken off the market because it increased the risk of cardiac valve fibrosis. Oraldopamineagonistscan be used as monotherapy but, as such, are rarely effective for more than a few years. Using these drugs early in treatment, with small doses oflevodopa, may be useful in patients at high risk of dyskinesias and on-off effects (eg, in patients < 60 years). However,dopamineagonists may be useful at all stages of the disease, including as adjunctive therapy in later stages. Adverse effects may limit the use of oraldopamineagonists. In 1 to 2% of patients, these drugs may cause compulsive gambling, excessive shopping, hypersexuality, or overeating, requiring dose reduction or withdrawal of the causative drug and possibly avoidance of the drug class. Pramipexoleandropinirole, given orally, can be used instead of or withlevodopain early Parkinson disease or, if necessary and not contraindicated, can be added to treatment in advanced disease. These drugs have a half-life of 6 to 12 hours and can be taken as immediate-release preparations 3 times a day. They can also be taken as sustained-release preparations once/day, helping minimize peaks and troughs in blood levels. Daytime sleepiness is a common adverse effect. Rotigotine, given transdermally once a day, provides more continuous dopaminergic stimulation than drugs given via other routes. Dose starts at 2 mg once a day and is usually increased to 6 mg once a day. Outside the US, higher doses (8 mg) may be recommended. 2 to 6 mg subcutaneously can be given up to 5 times a day as needed. A 2-mg test dose is given first to check for Orthostatic Hypotension . Blood pressure (BP) is checked in the supine and standing positions before treatment and 20, 40, and 60 minutes afterward. Other adverse effects are similar to those of other Apomorphinegiven by subcutaneous pump is available in some countries; it can be used instead of alevodopapump in patients who have advanced Parkinson disease and who are not candidates for functional surgery. Selective MAO-B inhibitors includeselegilineandrasagiline. Selegilineinhibits one of the two major enzymes that break downdopaminein the brain, thereby prolonging the action of each dose oflevodopa. In some patients with mild off effects,selegilinehelps prolonglevodopa’s effectiveness. Used initially as monotherapy,selegilinecontrols mild symptoms; as a result, use oflevodopacan be delayed by about 1 year. A dose of 5 mg orally 2 times a day does not cause hypertensive crisis, which, because of the drug'samphetamine-like metabolites, is sometimes triggered when patients taking a nonselective MAO inhibitor consume tyramine in foods (eg, some cheeses). Although virtually free of adverse effects,selegilinecan potentiatelevodopa-induced dyskinesias, mental and psychiatric adverse effects, and nausea, requiring reduction in thelevodopadose.Selegilineis also available in a formulation designed for buccal absorption (zydis-selegiline). Rasagilineinhibits the same enzymes asselegiline. It is effective and well-tolerated in early and late disease; uses ofrasagiline1 mg orally once a day are similar to those ofselegiline. Unlikeselegiline, it does not haveamphetamine-like metabolites, so theoretically, risk of a hypertensive crisis when patients consume tyramine is lower withrasagiline. Anticholinergic drugs can be used as monotherapy in early Parkinson disease and later to supplementlevodopa. They are most effective for tremor. Doses are increased very slowly. Adverse effects may include cognitive impairment and dry mouth, which are particularly troublesome for older patients and may be the principal problem with use of these drugs. Thus, anticholinergic drugs are usually used only in young patients with tremor-predominant Parkinson disease or with some dystonic components. Rarely, they are used as adjunctive treatment in older patients without cognitive impairment or psychiatric disorders. Some studies using a mouse model indicate that use of anticholinergic drugs should be limited because these drugs appear to increase tau pathology and neurodegeneration; degree of increase correlates with the drug's central anticholinergic activity ( Treatment references , Commonly used anticholinergic drugs include Benztropine: 0.5 mg at night up to 1 mg 2 times a day to 2 mg 3 times a day Trihexyphenidyl: 1 mg 3 times a day up to 2 to 5 mg 3 times a day Antihistamines with anticholinergic effects (eg,diphenhydramine25 to 50 mg 2 to 4 times a day, or phenadrine 50 mg orally once to 4 times a day) are occasionally useful for treating tremor. Anticholinergic tricyclic antidepressants (eg,amitriptyline10 to 150 mg orally at bedtime), if used for depression, may be useful as an adjunct tolevodopa. These drugs (eg,entacapone,tolcapone) inhibit the breakdown oflevodopaanddopamineand therefore appear to be useful adjuncts tolevodopa. They are used commonly in patients who have been takinglevodopafor a long time when response tolevodopais progressively wearing off at the end of dosing intervals (known as wearing-off effects), Entacaponecan be used in combination withlevodopaandcarbidopa. For each dose oflevodopataken, 200 mg ofentacaponeis given, to a maximum of 200 mg 8 times a day. Tolcaponeis a more potent COMT inhibitor because it can cross the blood-brain barrier; however, it is less commonly used because rarely, liver toxicity has been reported. It is an appropriate option ifentacaponedoes not sufficiently control off effects. The dose fortolcaponeis increased gradually from 100 up to 200 mg 3 times a day. Liver enzymes must be monitored periodically.Tolcaponeshould be stopped if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels increase to twice the upper limit of the normal range or higher or if symptoms and signs suggest that the liver is damaged. Opicaponeis a new 3rd-generation COMT inhibitor (recently approved in the US) that appears to be effective and safe in patients with Parkinson disease. Unliketolcaponeand likeentacapone,opicaponedoes not require monitoring with periodic laboratory tests or multiple oral dosing. Recommended dose is 50 mg at bedtime. If drugs are ineffective and/or have intolerable adverse effects, surgery, including deep brain stimulation and lesional surgery, may be considered. Deep brain stimulationof the subthalamic nucleus or globus pallidus interna is often recommended for patients withlevodopa-induced dyskinesias or significant motor fluctuations; this procedure can modulate overactivity in the basal ganglia and thus decrease parkinsonian symptoms in patients with Parkinson disease. For patients with tremor only, stimulation of the ventralis intermediate nucleus of the thalamus is sometimes recommended; however, because most patients also have other symptoms, stimulation of the subthalamic nucleus, which relieves tremor as well as other symptoms, is usually preferred. When the main problem is inadequate control of dyskinesias or when patients have an increased risk of cognitive decline, the globus pallidus interna is a good target. Lesional surgeryaims to stop overactivity directed to the thalamus from the globus pallidus interna; thalamotomy is sometimes done to control tremor in patients with tremor-predominant Parkinson disease. However, lesional surgery is not reversible and cannot be modulated over time; bilateral lesional surgery is not recommended because it can have severe adverse effects such as dysphagia and dysarthria. Lesional surgery involving the subthalamic nucleus is contraindicated because it causes severe ballismus. Patient selectionis the most important factor for successful functional surgery in Parkinson disease. Surgery is usually considered when drug treatment of disabling dyskinesias and/or motor fluctuations is ineffective or severely limited. Drug treatment may be inadequate because the drug has adverse effects that prevent further increases in thelevodopadose, which might lessen symptoms. Other selection criteria include Parkinson disease present for 5 to 15 years Patient age < 70 years No significant cognitive decline, no affective disorder, and, depending on life expectancy, no terminal disease (eg, cancer, chronic renal failure, liver failure, significant cardiopathy, uncontrolled diabetes mellitus or hypertension) Patients with cognitive impairment, dementia, or a psychiatric disorder are not suitable candidates for surgery because neurosurgery can exacerbate cognitive impairment and psychiatric disorders, and the risk of additional mental impairment outweighs the benefits of any improvement in motor function. MR-guided high-intensity focused ultrasound can be used to control severe tremor refractory to drugs in patients with Parkinson disease. With this procedure, the ventral intermediate nucleus of the thalamus can be ablated with minimal risk of hemorrhage and infection, which may occur when more invasive neurosurgical procedures are used. Studies are being done to determine the safety and efficacy of MR-guided high-intensity focused ultrasound that aims to treat tremor, rigidity, akinesia, and other cardinal signs of Parkinson disease by targeting the subthalamic nucleus and internal globus pallidus ( Treatment references ). Maximizing activity is a goal. Patients should increase daily activities to the greatest extent possible. If they cannot, physical or occupational therapy, which may involve a regular exercise program, may help condition them physically. Therapists may teach patients adaptive strategies and help them make appropriate adaptations in the home (eg, installing grab bars to reduce the risk of falls). To prevent or relieve constipation (which may result from the disease, antiparkinsonian drugs, and/or inactivity), patients should consume a high-fiber diet, exercise when possible, and drink adequate amounts of fluids. Dietary supplements (eg,psyllium) and stimulant laxatives (eg,bisacodyl10 to 20 mg orally once a day) can help. Because Parkinson disease is progressive, patients eventually need help with normal daily activities. Caregivers should be directed to resources that can help them learn about the physical and psychologic effects of Parkinson disease and about ways to help the patient function as well as possible. Because such care is tiring and stressful, caregivers should be encouraged to contact support groups for social and psychologic support. Eventually, most patients become severely disabled and immobile. They may be unable to eat, even with assistance. Because swallowing becomes increasingly difficult, death due to Aspiration Pneumonitis and Pneumonia is a risk. For some patients, a nursing home may be the best place for care. Before people with Parkinson disease are incapacitated, they should establish Advance Directives , indicating what kind of medical care they want at the end of life. 1.Yoshiyama Y, Kojima A, Itoh K, Uchiyama T, Arai K: Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model.Neurobiol Dis2012 45 (1):329–36, 2012. doi: 10.1016/j.nbd.2011.08.017 2.Yoshiyama Y, Kojima A, Itoh K, et al: Does anticholinergic activity affect neuropathology? Implication of neuroinflammation in Alzheimer's disease.Neurodegener Dis15 (3):140-148, 2015. doi: 10.1159/000381484 3.Moosa S, Martínez-Fernández R, Elias WJ, et al: The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson's disease.Mov Disord34 (9):1243–1251, 2019. doi: 10.1002/mds.27779 Epub 2019 Jul 10. 