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Algorithm For The Management Of Parkinson's Disease 7 |
The addition of amantadine or selegiline[115] also may result in mildly improved control of short-duration levodopa responses. If tremor is a significant problem, anticholinergic drugs (eg, trihexyphenidyl, benztropine) are an appropriate option, although anticholinergic side effects often limit their utility, especially in the elderly "Off"-phase dystonia also may respond to anticholinergic medications.
Subcutaneous apomorphine is favored by some clinicians outside the United States as rescue therapy for patients caught in a levodopa "off" state.[120] The response is rapid, developing in approximately 3.5 to 12.5 minutes and returning the patient to an "on" state comparable to their peak response with levodopa.[120] Although the response is brief (approximately 1 hour), it allows time for the patient's next dose of carbidopa-levodopa to take effect. Apomorphine's potential emetic effect necessitates concomitant use of domperidone, an investigational antiemetic drug that does not cross the blood-brain barrier and hence does not exacerbate parkinsonism.
Domperidone is available by prescription in most countries outside the United States.
OPTIMAL PEAK RESPONSE BUT UNPREDICTABLE "OFF." Most PD patients with fluctuations and intermittent loss of their levodopa effect have predictable "off" periods, although they may not perceive the pattern. To establish the pattern, it may be necessary to have the patient come to the office in the "off" state and then serially observe him as he cycles through the "on" response.
Unfortunately, occasional patients suffer from lack of predictability of their "off" states, including premature "wearing-off" and skipped-dose effects.
Management (breakout 16). Large neutral amino acid breakdown products of dietary protein, which inhibit levodopa transport,[121] may be a major factor in certain patients. Specific inquiry is necessary to establish the extent of meal effects. In appropriate patients, redistribution of dietary protein can prove beneficial.[122] Consuming most of the daily protein requirement during only one meal (often supper) may allow better responses after the other meals of the day. A dietitian should be involved in such modifications to assure that the minimum daily protein requirement continues to be met.
Adjunctive dopamine agonist therapy (bromocriptine, pergolide) may be particularly beneficial in patients with unpredictable "off" states. Delivery of these drugs to the brain does not appear to be compromised by meals and the response durations exceed those with levodopa.
Patients with unpredictable "off" periods sometimes get intermittently "trapped" in this state. Subcutaneously administered apomorphine and the adjunct antiemetic domperidone, where available can be an effective rescue therapy for such patients.[120]
Liquid carbidopa-levodopa may allow more consistent and reliable control of parkinsonism and is worth considering in patients with erratic control of their condition.[7] As discussed patients must be willing to accept the inconvenience of very frequent dosing (every 60 to 90 minutes) and daily preparation. Patients with unpredictable "off" states also may be appropriate candidates for many of the investigational protocols available at certain major medical centers.
FREEZING (MOTOR BLOCKS). Hesitancy or freezing of motor behavior can occur with any movement but is most apparent and troublesome to PD patients when it involves gait. In some patients, freezing is a manifestation of either an inadequate or an excessive dopamine effect. In certain other patients, it occurs independent of medications and is refractory to manipulation of dopamine.
Management (breakout 17). Attention to the timing of freezing in the levodopa response cycle determines the treatment strategy.
Freezing in conjunction with other prominent signs of parkinsonism during the time of peak levodopa effect suggests an underdosed state that may respond to larger individual doses of carbidopa-levodopa and other strategies described in the section, "Suboptimal peak response." Patients whose freezing is confined to their levodopa "off" states are often particularly responsive to more aggressive medical treatment, using the strategies outlined under "Optimal peak dose but wearing off." Although freezing may not respond as consistently to dopamine therapy as other motor manifestations, it certainly can be controlled with drugs in some patients.
Patients who already are receiving maximal medical treatment yet display freezing, even during their peak levodopa response times, present the most troublesome management problem. This scenario is most common in patients on adjunctive dopamine agonist therapy
(bromocriptine or pergolide), particularly if higher doses are employed. These patients may note improvement within a day or a few days after a 50% reduction in their dopamine agonist drug is tried. Further tapering reductions are appropriate in certain patients. A trial of levodopa dosage reduction or discontinuation of selegiline-which has the same effect as lowering levodopa dosage-may also be done on a trial basis.
Occasional patients improve with increased levodopa dosages, even if other signs of parkinsonism appear optimally controlled. Hence, a brief trial of incremental levodopa dosing may be indicated in some patients. Certain patients with refractory motor blocks may he candidates for clinical trials at major medical centers.
Regardless of the cause, gait freezing and similar motor blocks can be overcome by certain tricks that involve the use of sensory or mental imagery cues.[123] A patient unable to initiate the first step (freezing) often can circumvent this gait inhibition by one of several strategies, such as:
The general idea is to implement a conscious motor program to substitute for the malfunctioning subconscious automatic motor program. After experimenting with different ploys, patients typically find at least one strategy that is helpful.
Anxiety can exacerbate the tendency for motor blocks/freezing, If this is a major factor, measures aimed directly at treating the anxiety state may he appropriate (see the "Behavior impairment" subsection of the "Neuropsychiatric problems" section).
DYSKINESIAS. Dyskinesias can be drug or disease-related. If they include a prominent component of chorea, medications are implicated. If they are exclusively dystonic, this could either be caused by a disease-related condition or secondary to medications. Thus, dyskinesias an more appropriately addressed by separating them into those that are choreiform/choreodystonic vs those that are exclusively dystonic.(breakout 18).
Choreiform /choredystonic. Chorea in the context of PD is invariably related to medications, Frequently, a prominent dystonic component is seen in conjunction with the chorea; hence the term, "choreodystonic."
These choreodystonic dyskinesias occur in two patterns. The most common form is seen at the time of peak levodopa effect and has been termed "peak-dose dyskinesia" (or I-D-I response, a shorthand for "improvement-dyskinesia-improvement").[124] The first and most obvious approach to this problem is to modestly lower the individual uses of carbidopa-levodopa (eg, 25-mg decrements), Unfortunately, many patients have a very narrow therapeutic window, and even a small levodopa decrement can result in transition from a dyskinetic state to a relative "off" state. In this circumstance, one may consider adding or increasing a dopamine agonist medication (bromocriptine or pergolide), which allows a slightly tighter titration of the response. Patients who swing dramatically from severe dyskinesia and who have a short-duration response to the "off" state may find liquid carbidopa-levodopa to be a better option, with benefits and drawbacks as described above.
Choreodystonic dyskinesias are also seen in a second distinct pattern, in which these adventitious movements occur just at the beginning and again at the end of the levodopa response cycle. This has been termed "diphasic dyskinesia" or D-I-D response, a shorthand for "dyskinesia-improvement-dyskinesia").[124] This pattern is much less common than peak-dose dyskinesia and is often difficult to diagnose because the pattern may not he obvious, either to the patient or the clinician, The end-of-dose period of dyskinesias is typically more prolonged and troublesome than the initial dyskinetic period of the levodopa cycle.
Although this D-I-D pattern can be very difficult to treat, it may respond to simple measures if the dyskinesias are relatively mild. First, more frequent dosing of carbidopa-levodopa may allow a more continuous "on" state without periodically cycling through the dyskinetic phases. Obviously the timing of the doses should he based on the carbidopa-levodopa response duration. In a similar strategy to the one for treating "wearing-off" problems, a sustained-release formulation of carbidopa-levodopa may be substituted for the standard formulation, The addition of dopamine agonist therapy close titration, using liquid carbidopa-levodopa, may be options for some patients. Finally, subcutaneous apomorphine may provide a route of escape from the dyskinetic phase. The use of subcutaneous apomorphine (as described before) allows time for the next dose of carbidopa-levodopa to become clinically effective.
Occasional patients experience severe choreodystonic dyskinesias with a diphasic pattern, this can be very difficult to treat effectively. The initial descriptions of this clinical pattern[124] documented the failure of carbidopa-levodopa dosages administered at short intervals around the clock to effectively treat this problem. Although several carbidopa-levodopa doses at short intervals can successfully defer the end-of-dose dyskinetic period, this strategy fails after approximately tour to five overlapping doses.[124] At this point, patients typically begin to experience a sense of drug intoxication and, furthermore, note a decreasing threshold for dyskinesias with an inability to suppress them, despite even larger doses of carbidopa-levodopa.
For the diphasic dyskinesia pattern to become obvious, the levodopa dose must be adequate; too low a dose will simply result in dyskinesias, whereas a higher dose allows the full pattern to develop[124] The usual dosages of carbidopa-levodopa used to treat conventional parkinsonian motor problems are adequate for demonstration of the diphasic dyskinesia pattern (ie, 100 to 250 mg of levodopa). Typically, it is the end-of-dose dyskinetic period rather than the initial dyskinetic phase that is the more troublesome and sustained. It tends to occur at a fairly well-defined portion of the levodopa response cycle, usually 2 to 8 hours after a single dose of carbidopa-levodopa. One treatment strategy is to overlap four to five doses of carbidopa-levodopa at intervals that are
just long enough to preclude the development of the dyskinetic phase at the end of each dosage cycle[124] After the last dose, however, patients will cycle through the dyskinetic phase but at a relatively predictable time. Thus, they can arrange to be at home-and perhaps self administer a mild, short-acting tranquilizer such as alprazolam--during the time the dyskinetic period is expected.
Once they have cycled through this dyskinetic period, patients typically experience adequate control of their parkinsonian motor symptoms for the remainder of the day, although control is not quite as good as during the time of peak levodopa response. This control typically continues overnight and into the next morning. If left untreated, patients usually start to experience increasing motor manifestations of parkinsonism by mid to late morning, at which time they can again restart their levodopa cycle, taking four to five overlapping doses. Thus, with this strategy patients can attain good control of their parkinsonian symptoms for several midday hours and adequate control during other portions of the day, once they have cycled through their last dyskinetic period.
An alternative strategy for treating the severe diphasic choreodystonic dyskinesias is to switch the patient to dopamine agonist monotherapy (bromocriptine or pergolide). The transition can be difficult, as the dopamine agonist must be slowly introduced and the carbidopa-levodopa dosages concomitantly decreased. Eventually, as patients make the transition to bromocriptine or pergolide alone, they often will find that their parkinsonism is not as well controlled as with carbidopa-levodopa. The dyskinetic periods may be absent or substantially reduced in severity, however. To be effective, the bromocriptine or pergolide doses usually need to be higher than those employed when these drugs are used as adjunctive therapy with carbidopa-levodopa. For monotherapy, the usual range is 30 to 60 mg of bromocriptine or 3.0 to 6.0 mg of pergolide as monotherapy.
