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AN ALGORITHM FOR THE MANAGEMENT OF PARKINSON'S DISEASE a supplement of the American Academy of Neurology Reprinted in Neurology 1994;44:S1-S52. Editors: William Koller, M.D. Ph.D Dee Silver, M.D. Abraham Lieberman, M.D. EARLY PARKINSON'S DISEASE NON-PHARMACOLOGIC INTERVENTION The optimal approach to the management of early PD includes both pharmacologic and non-pharmacologic treatments. The best results will be achieved by addressing all the patient's needs. A good attitude on the part of the patient, a strong support system, and an experienced treating physician are all essential components for a successful outcome. Attention should not be focused solely on pharmacologic therapy. A team approach and a variety of therapeutic interventions are essential to optimal management. GROUP SUPPORT Patients and their families need help adapting to living with a chronic, progressive illness. Support groups offer psychologic and social benefits to both patient and family. Patients with PD benefit greatly from interaction with each other. Initially, individuals often tend to feel they are the only ones with this disease. Both the patient and the patient's family can benefit from participation in support groups. A national organization, the American Parkinson Disease Association (APDA), has chapters in most cities. Many of these groups meet on a monthly basis for discussion among themselves and, often, presentations by various professionals. The clinician should advise patients of the APDA's existence and encourage their participation. Because some patients with early disease might become discouraged when exposed to patients with more advanced disease, special APDA groups for individuals with young-onset PD have been formed to address their unique needs. Families of patients with PD also can benefit from group support. All family members are affected when a loved one is stricken by this disease, and they can react dysfunctionally if they do not have access to educational and support resources. EDUCATION Support groups provide practical information regarding PD. They often address issues such as the need for grab bars in the bathroom, a trapeze over the head of the bed, and velcro closures on clothing, which often are not mentioned by the physician. Patients who know as much as possible about their disease will receive the best treatment. PD newsletters from such national organizations as the United Parkinson's Foundation, the National Parkinson Foundation, and the APDA provide the education that allows patients to become advocates for their own causes. Information regarding available support organizations can be obtained by contacting: The American Parkinson Disease Association, Inc. 60 Bay Street, Suite 401 Staten Island, NY 10301 (800) 223-2732 National Parkinson Foundation, Inc. 1501 N.W. 9th Avenue, Bob Hope Road Miami, FL 33136-1494 (800) 433-7022 Parkinson's Disease Foundation 650 W, 168th Street New York, NY 10032 (212) 923-4700; (800) 457-6676 United Parkinson's Foundation 833 W. Washington Boulevard Chicago, IL 60607 (312) 733-1893 The book Parkinson's Disease: A Guide for Patient and Family, by R.C. Duvoisin also provides excellent information. The physician should let patients know about these invaluable educational resources. EXERCISE Daily exercise is one of the most beneficial things a patient can do for himself, can consist of stretching, walking, swimming or any activity the patient enjoys and will do regularly. More formal cardiovascular programs also are beneficial. Physicians should strongly encourage their patients to exercise. NUTRITION Patients with PD are at risk for nutritional disturbances for many reasons. Good nutrition is therefore essential to their overall well-being. Although no specific diet is required, patients should receive sufficient fiber and fluids to prevent constipation and enough calcium to avoid osteoporosis. Patients often will ask about the amount of protein needed in their diet, This is a concern only in individuals who are taking levodopa and experiencing erratic responses. It is not usually an issue in early PD. PHARMACOLOGIC INTERVENTION Once the diagnosis of PD has been made, the next decision is whether a patient should receive antiparkinsonian medication. Before the evidence of selegiline's possible role as a putative neuroprotective agent emerged, the decision to treat or not to treat PD was based solely on the degree of a patient's functional impairment, which in turn depended upon the particular symptoms the patient had (tremor, bradykinesia, gait impairment); whether the symptoms affected the dominant hand, nondominant hand, or both; and whether the patient was or was not working. If a neuroprotective therapy is definitely proven, then it should be started as soon as the diagnosis can he made. Once the degree of functional impairment is established, factors that affect a patient's ability to tolerate antiparkinsonian medication should be ascertained. One of the most important of these factors is whether the patient has cognitive impairment. Although these issues may seem straight forward, the decision to treat or not to treat is not easily reached, Assessing the severity of parkinsonian symptoms, functional impairment, and cognitive impairment is difficult. FUNCTIONAL IMPAIRMENT The presence of parkinsonian symptoms or functional impairment is implicit in diagnosing PD. If no symptoms or functional impairment were present, obviously the patient would not have come or been brought to a physician. Therefore, the issue is not whether functional impairment is present, but it is a question of degree and how the impairment can be assessed. Patients are most often aware of tremor, slowness of movement, and gait impairment. In most patients with early PD, the disease is predominantly unilateral, so that the degree of functional impairment often depends on which hand is affected. Thus, a patient with early PD with micrographia will have more functional impairment than a patient at the same stage of illness who has bradykinesia involving the nondominant, non-writing hand. As a result, patients with symptoms involving the dominant hand are more likely to seek treatment. PD in patients with early midline symptoms, manifested as gait impairment or postural instability, may evolve into a Parkinsonism Plus Syndrome (progressive supranuclear palsy and multiple system atrophies). At the time of diagnosis however, it may be impossible to distinguish a patient with Parkinsonism Plus Syndrome from one with PD. However, the initial pharmacologic approach is the same in these parkinsonian syndromes. Parkinsonian patients with symptoms of gait impairment or postural instability - manifested as festination, freezing, and impaired turning - should be treated. These symptoms can lead to falls and serious injury. Gait impairment and postural instability, if caused by early PD, are likely to respond to dopaminergic therapy. In advanced PD these symptoms may not respond as well to dopaminergic therapy. It is therefore conceivable that different mechanisms underlie these symptoms in early PD vs advanced PD. Tremor is present in approximately 70% of patients with PD. The tremor is usually asymmetric and present at rest. Therefore, unlike a tremor that manifests itself during movement, the tremor of PD, per se, is less likely to result in functional impairment. In some patients the rest tremors are associated with subjective distress, 'like a motor running all the time', and these tremors can be as disabling as a tremor that impairs motor skills. The resting tremor of PD may respond to carbidopa-levodopa, provided the dosage is high enough. For refractory cases of severe PD tremor, stereotactic thalamotomy is an effective option. The single most important social factor that determines whether or not a symptom will result in functional disability that requires treatment with carbidopa- levodopa is whether or not the patient is working. All things being equal, bradykinesia severe enough to cause marked slowing in walking and handling utensils is more likely to result in disability in someone who is working than someone who is not. Patients with PD who are working have to perform under a more strict time frame, and their symptoms can impair job performance. The Activities of Daily Living (ADL) scale of the United Parkinson Disease Rating Scale (UPDRS) is the most useful and uniform way to assess disability. The ADL scale evaluates speech, salivation, swallowing, handwriting, cutting food, handling utensils, hygiene, tuning in bed, falling, freezing, walking, tremor, and sensory symptoms. Careful questioning with the ADL scale as a framework often provide insight into how particular symptoms result in disability and provides a means of monitoring Parkinsonism over time. COGNITIVE IMPAIRMENT Cognitive impairment is an important modifier in determining pharmacologic intervention. Overt or subclinical cognitive impairment can alter a patient's response to antiparkinsonian drugs, especially anticholinergics and amantadine. In these patients, pharmacologic intervention can superimpose a toxic delirium on a substrate of disease related impairment. Cognitive impairment also can affect pharmacologic intervention indirectly. Patients with cognitive impairment may not perceive symptoms as acutely as patients without it. Such patients, although functionally impaired, sometimes insist they require no treatment. For symptoms such as tremor or bradykinesia, it may be best not to override the patient's wishes; but for gait impairment and postural instability, with their potential for serious disability, it may be necessary to do so. Such a decision obviously will be made with the approval of the patient's spouse and family. A related problem is affective disorders. Perception of impairment is often more exaggerated with patients who are anxious and depressed than those who are not. In some of these patients, counseling and antidepressants may be as effective as or more effective than antiparkinsonian drugs. Dementia occurs in 30 to 70% of patients with PD, depending on their age and duration of disease. How much of this dementia is disease-specific and how much comes from an overlap between PD and Alzheimer's disease is debated. Dementia is common in early PD, although mild cognitive impairment may be common. It is difficult to assess mild cognitive impairment and to distinguish it from a personality change, anxiety, depression, or preclinical dementia. Behavioral abnormalities, such as getting lost in familiar surroundings, failing to balance a checkbook, or personality changes, may be better indicators of cognitive impairment than cognitive testing in early PD. Thus, a patient who was confident, extroverted, and assertive and becomes uncertain, introverted, and cautious may be cognitively impaired in the absence of depression. The Mini-Mental State Examination (MMSE) is a simple means of measuring cognitive impairment. It assesses temporal and spatial orientation; digit span; and the ability to express and understand language, to follow commands, to remember, and to complete constructions. An abnormal MMSE suggests cognitive impairment but is not diagnostic of dementia. Conversely, a normal test does not exclude cognitive impairment. NEUROPROTECTION Until recently, all treatment of PD was symptomatic. Little was known about neuroprotection; slowing disease progression. A retrospective review of parkinsonian patients who were treated with the MAO-B inhibitor selegiline (formerly known as deprenyl), however, suggested that this drug may be a neuroprotective agent. Research subsequently showed that selegiline, by inhibiting MAO-B, prevented the development of MPTP-induced parkinsonism. This suggested that selegiline may be able to slow the progression of PD, possibly by reducing the generation of toxic free radicals. The hypothesis that selegiline may delay the progression of PD was tested in four prospective studies of patients with newly diagnosed PD who were not receiving carbidopa-levodopa. Patients in these studies were randomly assigned to either selegiline, 10 mg per day, or placebo and were followed until they required carbidopa-levodopa treatment. In all four studies selegiline slowed the rate of symptom development and delayed the need for carbidopa-levodopa by 50%. In all four studies however, selegiline was shown to have a symptomatic effect - which may be related to either its ability to block dopamine degradation in glial cells and neurons, thereby raising intracellular dopamine; or its ability to block dopamine reuptake, thereby raising levels of extracellular dopamine. The symptomatic improvement could be related to an indirect effect of selegiline on dopamine receptors. This symptomatic effect remains the focus of unresolved debate. Some think the symptomatic improvement is sufficient to obviate the need to invoke a neuroprotective effect as its mechanism of action. Others believe symptomatic improvement is not extensive enough to explain this effect. A retrospective postmortem study demonstrated greater preservation of dopaminergic neurons selegiline treated patients than in those not treated with the drug. Several other studies indicate selegiline may rescue dopaminergic neurons through a trophic effect, independent of inhibition of MAO-B. The delay in the progression of PD symptoms and the paucity of side effects associated with selegiline makes it a useful drug for initiating treatment in PD regardless of whether it exerts neuroprotective effect. Some clinicians think it is reasonable to continue selegiline once it has been started. If selegiline is later shown not to have a neuroprotective effect, little harm will have been done. If, on the other hand, the drug is later shown to have such an effect, patients who did not receive it may have needlessly suffered a greater loss of neurons than those who did. AGE CONSIDERATIONS The choice of drugs used in the treatment of PD is determined in part by the relative chronologic and biologic age of the patient. Age 60 is used here as an arbitrary cutoff. AMANTADINE Patients under 6O years of age. Amantadine is an antiviral agent discovered by chance to have antiparkinson activity. Its principal mechanism of action has not been established, but it is known to increase dopamine release, block dopamine reuptake, stimulate dopamine receptors, and-based on its clinical effects-to have peripheral anticholinergic properties. In uncontrolled studies, two thirds of patients receiving amantadine monotherapy showed improvement in akinesia, rigidity, and tremor. Amantadine appears to be more effective than anticholinergic drugs with regard to akinesia and rigidity but is less effective with regard to tremor. Placebo-controlled studies have confirmed improvement in all of the cardinal manifestations of PD. Benefit from amantadine is transient in some patients, with one third of patients showing reduced benefit within 4 to 8 weeks of initiation of treatment. In some studies, however, the benefit has been sustained for as long as 1 year. Amantadine is best used as short-term monotherapy for a period of 6 to 12 months in the treatment of patients with mild to moderate parkinsonism. Response frequently correlates with response to levodopa, making it particularly suitable for use before levodopa. If its effect wanes and other antiparkinsonian medications are added, amantadine should be discontinued to avoid unnecessary polypharmacy. Gradual withdrawal is recommended to prevent acute exacerbation of parkinsonian symptoms. Amantadine provides either modest or no significant additional benefit when added to levodopa treatment. Addition of levodopa to amantadine treatment however, produces a significant improvement. Amantadine has a plasma half-life of 10 to 28.5 hours and can be administered twice daily in dosages of 100 to 300 mg daily. Larger dosages provide no additional benefit and increase the likelihood of adverse effects. This drug's major advantage is a low incidence of side effects but, since it is excreted largely unchanged in the urine, it should be used with caution in patients with renal failure. Peripheral vascular side effects include livedo reticularis and ankle edema, but these are rarely severe enough to limit treatment. Confusion, hallucinations, insomnia, and nightmares can occur but are less common in patients aged 60 years or less, and they are more likely to occur when amantadine is used in combination with other antiparkinsonian drugs. Dry mouth and blurred vision are presumed to be peripheral anticholinergic side effects, but they seem to occur more commonly when amantadine is given in combination with anticholinergic drugs. In summary, amantadine is indicated for early treatment of PD in patients 60 years of age or less who have mild akinesia and rigidity and in whom tremor is not a major problem. Its therapeutic effects are relatively mild and might be limited in duration, but its low potential for side effects makes it particularly useful for early administration. Patients over 60 years of age. Amantadine may be used as early monotherapy for patients over age 60 with the same guidelines as for patients under aged 60 and under. Since the use of anticholinergic drugs is discouraged in this age group (discussion to follow), amantadine fills the need for a mild antiparkinsonian drug with low risk for adverse cognitive effects. Nonetheless, the risk for cognitive impairment with amantadine use is greater at this age, and appropriate caution should be exercised. In patients older than 60 years of age, an initial dose of 100 mg once daily should be administered for 1 week before increasing to 100 mg bid. Doses higher than 200 mg daily are discouraged in this age group ANTICHOLINERGIC DRUGS A balanced interaction exists between effects of dopamine and acetylcholine in the basal ganglia. In PD, dopamine depletion results in a state of cholinergic sensitivity, so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms. Centrally acting anticholinergic drugs, such as trihexyphenidyl and benztropine, continue to occupy a useful place in the treatment of PD in the era of levodopa and dopamine agonists. Although some anticholinergic drugs (e.g., benztropine) might augment the dopamine effect by inhibiting striatal presynaptic reuptake of dopamine, it is uncertain whether or not this contributes significantly to their mechanism of action. Patients under 60 years of age. Anticholinergic drugs should be considered for early monotherapy in patients 60 years of age or younger. Patients with tremor- predominant parkinsonism who are not significantly disturbed by akinesia are particularly good candidates for this approach. In many early studies, anticholinergic drugs were reported to be more effective for tremor and rigidity than for akinesia. Although this differential effect of anticholinergic drugs on specific parkinsonian signs has never been adequately studied and is not universally accepted, contemporary clinical experience has been that anticholinergic drugs are useful for resting tremor but of little value in the treatment of akinesia or impaired postural reflexes. Trihexyphenidyl is the most widely used anticholinergic drug, but little evidence suggests that one drug in this class is superior to another in terms of either therapeutic efficacy or side effects. Trihexyphenidyl is initiated at 0.5 to 1.0 mg twice daily and increased gradually to a dosage of 2 to 3 mg three times daily. Benztropine is given in dosages of 0.5 to 1.0 mg twice daily. As with amantadine, anticholinergic drugs should be discontinued gradually to avoid acute exacerbation of parkinsonism, even in patients in whom clinical response does not appear significant. Adverse side effects of anticholinergic drugs are common and often limit their use, irrespective of the patient's age. Peripheral antimuscarinic effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Particular caution should be exercised in the presence of prostatic hypertrophy or closed-angle glaucoma. Mild peripheral effects, such as dry mouth and blurred vision, often subside with continued treatment and do not limit therapy. CNS effects - such as sedation, dysphoric effects, memory impairment, acute confusion, and hallucinations - are much more troublesome and usually require discontinuation of medication. Both advanced age and dementia are risk factors for CNS toxicity; therefore, the use of anticholinergic drugs should be limited to patients aged 60 or younger. Even in patients without obvious cognitive side effects, improvement in short- term and long-term memory has been demonstrated after withdrawal of anticholinergic drugs. In summary, anticholinergic drugs are useful for the early treatment of PD in patients 60 years of age or younger in whom resting tremor is the predominant symptom. Because of the high incidence of peripheral and CNS side effects associated with these drugs, their use in patients without tremor and in patients above age 60 or with dementia is not recommended. Patients over 60 years of age. As discussed previously, the routine administration of anticholinergic drugs to patients above age 60 is not recommended. Nevertheless, these agents might be useful against specific symptoms in these patients, such as resting tremor that has been resistant to other treatment. If sialorrhea is to be treated with an anticholinergic drug in this population, one which acts peripherally, such as propantheline, should be considered to avoid CNS toxicity. janet [log in to unmask]