Parkinson`s Disease : Definition, Pathophysiology, Diagnosis and Treatment
Definition of Parkinson`s Disease: Idiopathic Parkinson’s disease (IPD) has highly characteristic neuropathologic findings and clinical presentation including motor deficits and, in some cases, mental deterioration. Pathophysiology of Parkinson`s Disease:
- Loss of nigrostriatal dopamine neurons results in reduction of cortical activation; virtually all the motor deficits of IPD are attributable to the marked loss in dopaminergic neurons projecting to the putamen. There is a positive correlation between the degree of nigrostriatal dopamine loss and disease severity.
- Drugs enhancing dopaminergic or inhibiting acetylcholine or glutamate neurotransmission have been successful in IPD therapeutics. Recent findings suggest that adenosine A2A receptor antagonists may also be promising.
- Activation of D2 receptors appears to be of primary importance for mediating both clinical improvement and some adverse effects (e.g., hallucinations). D1 receptors may be involved in producing dyskinesias.
- Degeneration of nigrostriatal dopamine neurons results in a relative increase of striatal cholinergic interneuron activity, which contributes to the tremor of IPD.
Clinical Presentation :
- IPD develops insidiously and progresses slowly. Clinical features are summarized in Table 53-1. Initial symptoms may be sensory, but as the disease progresses, one or more classic primary features present (e.g., resting tremor, rigidity, bradykinesia, postural changes). Other characteristics include micrographia, decreased facial animation (hypomimia) and blink rate, shuffling gait, and decreased dexterity.
- Resting tremor is typical of IPD and often is the sole presenting complaint. However, only two-thirds of IPD patients have tremor on diagnosis, and some never develop this sign. Tremor is present most commonly in the hands, often begins unilaterally, and sometimes has a characteristic â€œpill-rollingâ€ quality. The resting tremor is usually abolished by volitional movement and is absent during sleep.
- Muscular rigidity involves increased muscular resistance to passive range of motion and can be cogwheel in nature. Postural instability may lead to falls.
- Intellectual deterioration is not inevitable, but some patients deteriorate in a manner indistinguishable from Alzheimer’s disease.
Diagnosis of Parkinson`s Disease :
- Diagnostic criteria specify that at least two of the following be present: (1) limb muscle rigidity, (2) resting tremor (at 3 to 6 Hz and abolished by movement), (3) bradykinesia, or (4) postural instability.
- A number of other conditions must also be excluded. Medication-induced parkinsonism must be ruled out (e.g., antipsychotics, antiemetics, or metoclopramide). Other diagnostic criteria include lack of other neurologic impairment and responsiveness to levodopa.
- Treatment algorithms for early and late IPD.
- A summary of available antiparkinsonian medications.
- In patients with mild symptoms, medications are often not needed if disabilities have not developed. Many patients have only mild slowness and resting tremor that can be managed effectively with anticholinergics or amantadine.
- The most effective treatment for IPD is replacement of the natural neurotransmitter dopamine by giving its immediate precursor, levodopa. Although levodopa is more effective than other available medications, concern for possible long-term risks causes some clinicians to limit its use.
- The decision to incorporate levodopa or dopamine agonist therapy is determined by advancing disability and ineffectiveness of alternative medications in providing adequate symptom control.
- L-dopa and dopaminergic agonists may cause psychiatric symptoms, including compulsive behaviors, delirium, agitation, paranoia, delusions, and hallucinations. These problems can be managed using the guidelines and antipsychotic medication as summarized.
- Anticholinergic drugs can be effective for tremor and dystonic features in some patients but rarely show substantial benefit for bradykinesia or other disabilities. They can be used as monotherapy or in conjunction with other antiparkinsonian drugs. They differ little from each other in therapeutic potential or adverse effects.
- Anticholinergic side effects include dry mouth, blurred vision, constipation, and urinary retention. More serious reactions include forgetfulness, sedation, depression, and anxiety. Patients with preexisting cognitive deficits and advanced age are at greater risk for central anticholinergic effects.
- Amantadine is often effective for mild symptoms, especially tremor. It may also decrease dyskinesia at relatively high doses (400 mg/day).
- Its precise mechanism of action is unknown but may involve dopaminergic or nondopaminergic mechanisms such as inhibition of N-methyl-d-aspartate receptors.
- Adverse effects include sedation, vivid dreams, dry mouth, depression, hallucinations, anxiety, dizziness, psychosis, and confusion. Livedo reticularis (a diffuse mottling of the skin) is a common but reversible side effect.
- Doses should be reduced in patients with renal dysfunction.
Levodopa and Carbidopa/Levodopa
- Levodopa, the most effective drug available, is the immediate precursor of dopamine. It crosses the blood-brain barrier, whereas dopamine does not.
- The decision to start L-dopa as soon as the diagnosis is made or only when symptoms compromise social, occupational, or psychological well-being has generated controversy. A study is under way that should assist in making an informed decision.
- In the central nervous system (CNS) and elsewhere, levodopa is converted by l-amino acid decarboxylase (l-AAD) to dopamine. In the periphery, l-AAD can be blocked by administering carbidopa, which does not cross the blood-brain barrier. Carbidopa therefore increases the CNS penetration of exogenously administered levodopa and decreases adverse effects (e.g., nausea, vomiting, cardiac arrhythmias, postural hypotension, vivid dreams) from peripheral levodopa metabolism to dopamine.
- Starting levodopa at 200 to 300 mg/day in combination with carbidopa often achieves adequate relief of disability. The usual maximal dose of levodopa is 800 mg/day.
- About 75 mg of carbidopa is required to prevent peripheral adverse effects, but some patients may benefit from as much as 150 mg/day. Carbidopa/levodopa is most widely used in a 25-mg/100-mg tablet, but 25-mg/250-mg and 10-mg/100-mg dosage forms are also available. Controlled-release preparations of carbidopa/levodopa are available in 50-mg/200-mg and 25-mg/100-mg strengths. If peripheral adverse effects are prominent, 25mg carbidopa (Lodosyn) tablets are available.
- Between 5% and 10% of IPD patients develop involuntary movements or short-duration responses with each year of levodopa treatment. Movement complications associated with long-term use of carbidopa/levodopa and their suggested treatments.
- End-of-dose deterioration (â€œwearing offâ€) has been related to increasing loss of neuronal storage capability for dopamine. Carbidopa/levodopa can be given more frequently or a controlled-release product can be tried. Some patients taking sustained-release forms require increased levodopa doses because of decreased bioavailability, and a conventional carbidopa/levodopa dose in the morning may be needed for more rapid absorption and response. Dopamine agonists also can be added to carbidopa/levodopa to treat wearing off.
- Monoamine oxidase B (MAO-B) inhibitors (selegiline) and the catechol-O-methyltransferase (COMT) inhibitors (tolcapone and entacapone) extend the action of levodopa, as discussed later in this chapter.
- Rapid fluctuations from â€œonâ€ to â€œoffâ€ motor states can develop in patients taking levodopa chronically. Infusions of L-dopa or long-acting dopaminergic agonists tend to alleviate these fluctuations. The addition of MAO inhibitors or COMT inhibitors also may be beneficial. Drug-free periods (drug holidays) have not proven useful as therapeutic interventions because of the discomforts, risks, and limited gains observed in most patients.
- Dyskinesias and dystonias are usually associated with peak antiparkinsonian benefit. In this situation, the use of smaller, more frequent levodopa doses, sustained-release preparations, or addition of a dopamine agonist may be helpful.
- Psychiatric side effects of levodopa include delirium, agitation, paranoia, delusions, and hallucinations. These are especially likely in older patients and those with underlying confusion or dementia. Clozapine in low doses may improve psychotic symptoms while improving tremor and other motor symptoms. Quetiapine is also safe and effective. Olanzapine and risperidone may improve psychotic symptoms but often worsen parkinsonian features.
- There is marked intra- and intersubject variability in the time to peak plasma concentrations after oral levodopa, and there may be more than one peak plasma concentration after a single dose because of erratic gastric emptying. Meals delay but antacids promote gastric emptying. Levodopa is primarily absorbed in the proximal duodenum by a saturable large neutral amino acid (LNAA) transport system. Dietary LNAAs can compete for this site and compete with levodopa for transport into the brain. The elimination half-life of levodopa is about 1 hour and is extended to about 1.5 hours with carbidopa.
- Levodopa should not be administered with MAO-A inhibitors, because of a risk of hypertensive crisis, or with traditional antipsychotic agents, because of possible antagonism of levodopa efficacy.
Monoamine Oxidase B Inhibitors
- Selegiline (deprenyl; Eldepryl) is an irreversible MAO-B inhibitor that blocks dopamine breakdown and can modestly extend the duration of action of levodopa (up to 1 hour). It often permits reduction of levodopa dose by as much as one-half.
- Selegiline also increases the peak effects of levodopa and can worsen preexisting dyskinesias or psychiatric symptoms such as delusions and halluci- nations.
- Metabolites of selegiline are l-methamphetamine and l-amphetamine. Adverse effects are minimal and include insomnia and jitteriness.
- Studies evaluating its neuroprotective properties suggest that selegiline can delay the need for levodopa by about 9 months and has symptomatic effects, but there is no firm evidence that it can slow neurodegeneration.
- Rasagiline, another MAO-B inhibitor, has similar effects as selegiline in enhancing L-dopa effects and modest beneficial effect as monotherapy.
- Tolcapone (Tasmar) and entacapone (Comtan) are used only in conjunction with carbidopa/levodopa to prevent the peripheral conversion of levodopa to its metabolite 3-O-methyldopa (3OMD) and thus prolong the action of levodopa, that is, increas â€œonâ€ time by about 1 hour. These agents significantly decrease â€œoffâ€ time and decrease levodopa requirements. Concomitant use of nonselective MAO inhibitors should be avoided to prevent inhibition of the pathways for normal catecholamine metabolism.
- COMT inhibition is more effective than controlled-release carbidopa-L-dopa in providing consistent extension of effect and avoids the delay in time to maximal effect seen with controlled-release L-dopa products. It is unclear whether use of these adjunctive agents will be more beneficial and cost effective than maximizing therapy with carbidopa/L-dopa alone.
- The starting and recommended dose of tolcapone is 100 mg three times daily as an adjunct to carbidopa/levodopa. Its use is limited by the potential for serious liver dysfunction; several deaths have been reported. Strict monitoring of liver function is required, and tolcapone should be discontinued if liver function tests are above the upper limit of normal or any signs or symptoms suggestive of hepatic failure exist.
- Because entacapone has a shorter half-life, 200 mg is given with each dose of carbidopa/levodopa up to 8 times a day. Dopaminergic adverse effects may occur and are managed easily by reducing the carbidopa/levodopa dose. Brownish-orange urine discoloration may occur (as with tolcapone), but there is no evidence of hepatotoxicity from entacapone.
- The ergot derivatives pergolide (Permax) and bromocriptine (Parlodel) and the nonergots pramipexole (Mirapex) and ropinirole (Requip) are beneficial adjuncts in patients with deteriorating response to levodopa, those experiencing fluctuation in response to levodopa, and those with limited clinical response to levodopa due to inability to tolerate higher doses. They decrease the frequency of â€œoffâ€ periods and provide a levodopa-sparing effect.
- The dose of dopamine agonists is best determined by slow titration to enhance tolerance and to find the least dose that provides optimal benefit.
- Pergolide with levodopa is similar or perhaps more efficacious with fewer side effects than bromocriptine with levodopa.
- When used as monotherapy, pergolide, pramipexole, and ropinirole seem to be more effective than bromocriptine as alternatives to levodopa, but only pramipexole and ropinirole are approved for monotherapy.
- Using the combination of levodopa with a dopamine agonist or dopamine agonist monotherapy as initial treatment revealed a decreased risk for the development of response fluctuations. This has raised the question of whether initial therapy of IPD should consist of dopamine agonist monotherapy. Because younger patients are more likely to develop motor fluctuations because of their longer life expectancy, dopamine agonists may be preferred in this population. Older patients are more likely to experience psychosis from dopamine agonists; therefore, carbidopa/levodopa may be the best initial medication, particularly if cognitive problems or dementia is present.
- There is no rationale at present to choose one dopamine agonist over another on the basis of receptor specificity. A recommended initial dose of bromocriptine is 1.25 mg once or twice daily; the dose should be escalated slowly by 1.25 to 2.5 mg/day every week and maintained at the minimum effective dose. Average daily doses less than 30 mg may be effective for several years in many patients, but some patients require up to 120 mg/day.
- A recommended initial dose of pergolide is 0.05 mg/day for 2 days, gradually increasing by 0.1 to 0.15 mg/day every 3 days over a 12-day period. If higher doses are needed, the dose may be increased by 0.25 mg every 3 days until symptoms are eliminated or adverse effects occur. The mean therapeutic dose in most clinical trials was approximately 3 mg/day.
- Pramipexole is initiated at a dose of 0.125 mg three times daily and increased every 5 to 7 days as tolerated. In a fixed-dose study, doses greater than 3 mg/day were no more effective than 1.5 mg/day and were associated with more frequent adverse effects. It is primarily renally excreted, and the initial dose must be adjusted in renal insufficiency.
- Ropinirole is initiated at 0.25 mg three times daily and increased by 0.25 mg three times daily on a weekly basis to a maximum of 24 mg/day. It is metabolized by cytochrome P450 1A2; fluoroquinolones and smoking may alter ropinirole clearance.
- Apomorphine is a dopamine agonist that will soon be released in the United States as a subcutaneous injection. Cabergoline is a selective D2 ergot agonist with a half-life of 70 hours that is available in the United States for treatment of hyperprolactinemia.
- Nausea is the most common side effect, followed by sedation, light-headedness, and vivid dreams. Asymptomatic postural hypotension is common but does not always require medication adjustment. CNS effects (e.g., confusion, hallucinations, and sedation) are often dose limiting. Pedal edema can also occur. The ergot dopamine agonists are associated rarely with pleuropulmonary fibrosis, and recently, cases of cardiac valvulopathy have been reported with pergolide.
EVALUATION OF THERAPEUTIC OUTCOMES
- Patients and caregivers should be educated so that they can participate in treatment by recording medication administration times and duration of â€œonâ€ and â€œoffâ€ periods.
- Symptoms, side effects, and activities of daily living must be scrupulously monitored and therapy individualized.