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Algorithm For The Management Of Parkinson's Disease 2

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FUNCTIONAL IMPAIRMENT. The presence of parkinsonian symptoms or functional impairment is implicit in diagnosing PD.[7-8] 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.[3-4] 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).[9] 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.[10] Tremor is present in approximately 70% of patients with PD.[2] 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.[10,11] 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.[2] 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.[12-15] 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 uncommon in early PD, although mild cognitive impairment maybe common.[4,5] 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.[17] Research subsequently showed that selegiline, by inhibiting MAO-B, prevented the development of MPTP-induced parkinsonism.[16] 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.[10,11,18,19] 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.[20-21]

The symptomatic improvement could be related to an indirect effect of selegiline on dopamine receptors.[22] 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.[23] Others believe symptomatic improvement is not extensive enough to explain this effect.[10] A retrospective postmortem study demonstrated greater preservation of dopaminergic neurons selegiline treated patients than in those not treated with the drug.[24] Several other studies indicate selegiline may rescue dopaminergic neurons through a trophic effect, independent of inhibition of MAO-B.[25-26] 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 (breakouts 3A and 3B)

AMANTADINE. Patients <60 years of age. Amantadine is an antiviral agent discovered by chance to have antiparkinson activity.[27] Its principal mechanism of action has not been established, but it is known to increase dopamine release, block dopamine reuptake, stimulate dopamine receptors, [28-29] and-based on its clinical effects-to have peripheral anticholinergic properties.[30] In uncontrolled studios, two thirds of patients receiving amantadine monotherapy showed improvement in akinesia, rigidity, and tremor.[27,31] Amantadine appears to be more effective than anticholinergic drugs with regard to akinesia and rigidity[32] but is less effective with regard to tremor.[33] Placebo-controlled studies have confirmed improvement in all of the cardinal manifestations of PD.[34,35] Benefit from amantadine is transient in some patients,[36,37] with one third of patients showing reduced benefit within 4 to 8 weeks of initiation of treatment.[27] In some studies, however, the benefit has been sustained for as long as 1 year.[32] 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,[32] 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.[29,38,39] Addition of levodopa to amantadine treatment however, produces a significant improvement.[38,40] 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[41] 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 >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

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