OPTIMAL PEAK RESPONSE BUT "WEARING OFF." Adjustment of medications to obtain an optimal peak effect generally is the initial strategy. Subsequently, the focus shifts to the levodopa response duration. Patients with "wearing off" of their levodopa effect before the next dose may respond to one of several strategies (breakout 15). Substituting sustained-release caribidopa-levodopa for the standard formulation typically will add 60 to 90 minutes to the response duration.[116] Although there is not a direct milligram to milligram correspondence between the standard and CR formulations of carbidopa-levodopa, simple dosing guidelines allow a rapid transition. In converting to the CR formulation, the individual doses must be 30 to 50% higher to achieve the same peak effect.[116] The interval between doses is adjusted to correspond with the estimated response duration. Simply shortening the interval between carbidopa-levodopa doses (standard or CR formulation) is a common sense strategy for countering "wearing-off" effects. Optimally, the next dose should be given just before the effects from the last dose have worn off. Patients with short-duration responses often respond well to adjunctive dopamine agonist therapy with bromocriptine[117] or pergolide.[118] The dosage is started at subtherapeutic levels (1.25 mg of bromocriptine or 0.05 mg of pergolide daily), and hence the levodopa dosage should be maintained until a clinical response develops. Subsequently, the levodopa dosage can be gradually lowered as the clinical effects from bromocriptine or pergolide become apparent. The clinically effective range of dosages is approximately 15 to 50 mg of bromocriptine or 1.5 to 5.0 mg of pergolide daily (divided). Occasionally, switching from one dopamine agonist to another (eg, bromocriptine to pergolide using a 10-to-1 potency ratio is helpful). The expense of the highest doses of these drugs may be prohibitive, however, for certain patients. In patients with severe fluctuations, if titration cannot be adequately achieved with the above measures, transition to liquid carbidopa-levodopa may be considered.[119] Very close titration is possible with this strategy, resulting both in less "off" time and potentially fewer dyskinesias (see below) The disadvantages are: a much shorter response duration (60 to 90 minutes), the requirement for the patient to prepare the liquid formulation, and the lack of stability of levodopa in solution. This last problem is countered by adding ascorbic acid for stabilization, but even then, the liquid preparation cannot be carried over from one day to the next. The usual mixture is prepared by pulverizing with mortar and pestle, ten 25/100 standard carbidopa-levodopa tablets and 2 g of ascorbic acid, which are then added to 1 liter of tap water.[119] The transition from tablet to liquid carbidopa-levodopa is made by administering small levodopa doses at 60- to 90-minute intervals, with the total daily dose similar to that given with tablets; further titration is based on the response. Several investigational drugs are under development for treatment of response fluctuations. These include novel dopamine agonists, catechol-O-methyl transferase inhibitors, and selective MAO inhibitors. Patients who experience fluctuations may wish to take advantage of the opportunities for entry into investigational protocols, which are available at many major medical centers. 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: _ stepping toward a target on the ground; _ stepping over a cane laid on the floor in front of the foot[123]; or _ taking the first steps with a stiff-legged, long-striding military gait. 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. Exacerbated by anxiety. Regardless of the type or pattern. choreodystonic dyskinesias can be unmasked or worsened by anxiety- provoking situations. If this is a frequent problem for the patient, intervention directed at neuropsychiatric issues may be appropriate. Dystonic movements. Dystonia in the absence of chorea is common in PD and can be caused by the disease process, per se, rather than a medication effect. Dystonia is commonly related to drug action, however. Prototypic is the isolated dystonic deviation of the toes or cramping of the legs that occasionally occurs in undertreated patients. Often, this will occur with other signs of undertreated parkinsonism. In this case, the usual strategies for improving PD motor control are appropriate. In certain patients, painful dystonia of the lower extremities is particularly a problem upon awakening in the morning (early morning foot dystonia), before the initial morning dose of carbidopa-levodopa can take effect. One option is to administer a dose of CR carbidopa-levodopa at bedtime. The effects may not be sufficiently long-lasting to carry the patient to the following morning, however. Administration of a dose of carbidopa-levodopa in the early morning, before the patient is scheduled to rise from bed, can be effective but requires the patient to set an alarm to awaken. The addition of bromocriptine or pergolide, with their longer-lasting effects, also may prove beneficial, particularly if one of the doses is administered at bedtime. Some patients experience painful or uncomfortable dystonia at the end of their levodopa response cycle. Several options are available, as described in the section "Optimal peak response but "wearing off." This is also one circumstance, apart from tremor, in which an anticholinergic drug may be helpful. Lithium may be helpful for painful "off"-period dystonia and can be tried when all other methods have failed. Botulinum toxin injection can be used to treat sustained focal dystonias of the foot. In some patients dystonia may be secondary to their medications. If it is present at the time of peak levodopa effect, a reduction in the individual doses of carbidopa-levodopa should result in resolution. If it occurs during the "off" period as a "wearing-off" phenomenon, strategies can be employed to increase "on" time (see the section "Optimal response but wearing off"). NEUROPSYCHIATRIC PROBLEMS The neuropsychiatric manifestations of PD and of the medications used to treat it can be ever more disabling than the motoric dysfunction seen in this illness. In approaching the management of this group of symptoms, it is important to keep in mind that some of them, such as hallucinations, usually are induced by medication, while others, such as depression and "off"-period anxiety, typically are not directly related to drugs. Still a third group of neuropsychiatric symptoms, most notably memory loss, confusion, ant agitation occur independent of medication in some patients but can be caused or exacerbated by antiparkinsonian agents in others. Thus, in devising a rational approach to the treatment of these behavioral syndromes, a critical decision must be made as to whether to add psychoactive medications, reduce the dosage of antiparkinsonian agents, or do both. COGNITIVE IMPAIRMENT. The incidence of dementia in patients with PD has been variously estimated, but most studies place it in the range of 15 to 20%[125,126] in a typical clinic population. Its prevalence increases with disease duration and with advancing age and contributes to mortality. In one recent study,[125] dementia developed in 65% of patients with PD by the time they reached 85 years of age. Memory loss is one of the most noticeable manifestations of dementia in patients with PD.[127] Some patients also manifest the phenomenon of bradyphrenia a slowing of cognitive processes that is out of proportion to their general level of cognitive function.[128] Not only does primary dementia appear in patients with PO but these individuals especially those over age 65, may also suffer from other dementing illnesses, such as Alzheimer's disease or multi-infarct dementia. Unlike drug-induced cognitive symptoms, those caused by PD itself are not amenable to therapy (breakout 19). However, parkinsonian patients with dementia are especially prone to experience further memory loss or confusion when treated with antiparkinsonian drugs. As I will discuss, reduction or cessation of these drugs is a valid therapeutic option in this circumstance. Drug-induced cognitive impairment can take the form of impaired memory or confusion. Memory deficit as a manifestation of antiparkinsonian drugs is almost always caused by agents having anticholinergic properties--most notably drugs such as trihexyphenidyl or benztropine, but also agents such as amantadine and the tricyclic antidepressants. This effect appears to be especially prominent in the elderly, which suggests that the primary antiparkinsonian anticholinergic drugs should be avoided in this group and that even these agents with milder anticholinergic effects should he used with great caution. The management of medication-induced memory deficit consists of reducing or elimination the offending medication. In patients who take more than one class of anticholinergic preparation, the agent with the most potent anticholinergic properties-the anticholinergic antiparkinsonian agents-should be eliminated or reduced first, followed by the tricyclic antidepressants and finally amantadine. A tricyclic antidepressant such as amitriptyline occasionally can be replaced with one with less anticholinergic potency, such as nortriptyline, but just as often, total discontinuance of drugs with any anticholinergic effect, however mild, is required. Confusion can be induced by anticholinergic medications and by those which are dopaminergic, as well. Thus, selegiline, the dopamine agonists (bromocriptine and pergolide), and carbidopa-levodopa must be considered as potential causes of this symptom. When confusion develops in a patient taking several of these preparations, a decision must be made as to which should be discontinued or reduced first. A reasonable guideline is to discontinue first the agent that has the greatest potential for causing confusion but has a relatively smaller impact on the motoric symptoms of PD. In this approach, the anticholinergic preparations should he the first to be discontinued, followed by selegiline, tricyclic antidepressants, amantadine, and then the dopamine agonists. If confusion persists despite discontinuance of these preparations, or if the patient has not been receiving any of them, the carbidopa-levodopa dosage must then be reduced. In most patients with moderate to advanced PD, total discontinuance of carbidopa-levodopa is not feasible because of the reemergence of severely disabling motoric symptoms. Instead, a gradual downward titration of dosage is recommended, aiming at an amount low enough to relieve confusion but high enough to provide some benefit for motor skills and ambulation. Unfortunately, in some patients confusion is a direct consequence of the disease process and no medication adjustment is adequate to reduce these symptoms. PSYCHOSIS. Psychosis in PD can take many forms[129] and is almost always drug-induced. Two of the most common psychotic manifestations are vivid dreams and hallucinations (breakout 20). The management of the former is handled in the "Sleep disorders" algorithm. The latter is covered under a separate heading in the "Neuropsychiatric problems" algorithm. BEHAVIORAL IMPAIRMENT. Behavioral impairment in PD can take the form of agitation, depression, anxiety, and panic attacks (breakout 21). Agitation. Agitation can occur spontaneously in PD or result from virtually any of the antiparkinsonian medications. * Primary. The treatment of agitation, when it occurs without relation to antiparkinsonian medication, involves the administration of anxiolytic agents. The benzodiazepines, especially alprazolam, are particularly useful. Diazepam and lorazepam can he used for this purpose, as well. Buspirone, a 5-HTia serotonin agonist, is also an effective anxiolytic, but because of its dopamine-blocking potential it probably should not be the first agent used in a patient with PD. * Medication induced. When it appears that agitation is an adverse effect of medication, adjunctive antiparkinsonian agents should be discontinued in order of their potential to have caused this syndrome. Selegiline, especially in a patient already receiving levodopa, should be discontinued first, followed by amantadine, dopamine agonists, and anticholinergic agents. It is worth noting because of their profound effect on cognitive processes, are the first to be discontinued when memory loss is the target symptom but are among the last to be discontinued when agitation is the problem. If none of these preparations is in use, or if all have been discontinued without improvement in agitation, then carbidopa-levodopa must be carefully titrated downward, in hope of improving agitation without allowing the reemergence of serious motor disability.; In addition to these measures, a careful review should be made of other non-PD medications that may have the potential to produce or enhance agitation. Certain patients who are receiving inadequate dosages of dopaminergic medications or who are experiencing "wearing off" of the levodopa effect become very anxious and might appear agitated. This must be distinguished from primary agitation. Depression. Depression is extremely common in PD. In a recent study the incidence of depression in PD was found to be 47%.[130] The diagnosis of an affective disorder in PD can be difficult, however, because many of the clinical manifestations of depression--such as slowness, poor concentration, sleep disturbance, and loss of energy--can be signs of PD itself. Starkstein et al.[131] confirmed that motor retardation, loss of energy, and early morning awakening were no more common in nondepressed than depressed patients with PD. On the other hand, depressive symptoms--such as worrying, brooding, loss of interest, suicidal tendencies, social withdrawal, loss of libido, and initial or middle insomnia--among others, were more common in depressed than nondepressed patients. Having made a diagnosis of depression, it is important to recognize that in some patients, mood changes occur in synchrony with motor fluctuations, resulting in the patient's feeling depressed only when he or she is in an "off" state.[132] In this circumstance, management consists of techniques to reduce motor fluctuations (see the "Motor problems" section of the algorithm). In parkinsonian patients with sustained depression, a variety of therapeutic approaches can be used. In some situations counseling serves as an important adjunct to other therapies, but a major depressive disorder usually requires pharmacologic therapies, physiologic therapies, or both. The tricyclic antidepressant medications are a mainstay of pharmacotherapy for these patients.[133] Amitriptyline is among the least expensive of this class of agents. Its sedative properties can be a distinct advantage when it is administered at bedtime to patients with disturbed sleep. The anticholinergic and orthostatic side effects of this drug, however, will often limit its effectiveness or prevent its use, especially in elderly patients or those with moderately severe PD. Nortriptyline is often a better choice, given its lower anticholinergic potency. An initial dose of 20 to 40 mg is appropriate, with the ultimate dosage seldom exceeding 100 mg per day in the PD population. While it is not as sedating as amitriptyline, nortriptyline is still useful in encouraging sleep when given as a bedtime dosage. The selective serotonin reuptake inhibitors--such as fluoxetine, sertraline, and paroxetine-- John Cottingham NEW ADDRESS: [log in to unmask]