Apomorphine test in de novo Parkinson's disease.

We administered apomorphine, a powerful dopaminergic agonist, subcutaneously to 25 untreated patients with parkinsonian features and evaluated motor response with the aim of discriminating idiopathic Parkinson's disease (IPD) from multiple system atrophy and progressive supranuclear palsy. The response to apomorphine was strongly predictive of responsiveness to subsequent levodopa follow-up and of the final diagnosis, made on the basis of both clinical and instrumental evaluation. Our data confirm that the apomorphine test is helpful in the differential diagnosis of IPD.     

Challenge tests to predict the dopaminergic response in untreated Parkinson's disease

To clarify the predictive role of dopaminergic challenge tests, we compared the responses to subcutaneous apomorphine and oral levodopa with the therapeutic effect of ongoing levodopa treatment in 45 previously untreated patients with idiopathic Parkinson's disease. The response to long-term levodopa was accurately predicted by apomorphine in 67% (30) of patients and by levodopa in 80% (35) of patients. There were nine cases without a definite response to sustained levodopa, four in patients who developed atypical clinical features during the period of follow-up. These tests have a predictive value for subsequent dopaminergic responsiveness and may help in the early differential diagnosis of parkinsonian syndromes.     

Comparison of motor response to apomorphine and levodopa in Parkinson''s disease.

The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.     

Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.     

Systematic review of acute levodopa and apomorphine challenge tests in the diagnosis of idiopathic Parkinson's disease

OBJECTIVES: To perform a systematic review of studies examining the diagnostic accuracy of acute challenge tests with levodopa and/or apomorphine in parkinsonian syndromes to assess their value in the diagnosis of idiopathic Parkinson's disease. METHODS: A literature search including Medline and the Cochrane Library was performed for studies published in any language comparing acute levodopa and/or apomorphine response with chronic levodopa therapy in parkinsonian syndromes. Abstracted sensitivity and specificity data were summarised using variance weighting and conditional logistic regression for studies comparing two challenge tests. RESULTS: Thirteen studies were located: four examining de novo patients and nine examining patients with well established idiopathic Parkinson's disease and non-parkinsonian conditions. Despite the significant heterogeneity in the methodologies employed, the comparable results suggest that this had little effect on the accuracy of the tests. The sensitivity for the diagnosis of established idiopathic Parkinson's disease was: apomorphine 0.86 (95% confidence interval (95% CI) 0.78-0.94), acute levodopa 0.75 (95% CI 0.64-0.85), and chronic levodopa therapy 0.91 (95% CI 0.85-0.99). The specificity for the diagnosis of established idiopathic Parkinson's disease was: apomorphine 0.85 (95% CI 0.74-0.96), acute levodopa 0.87 (95% CI 0. 77-0.97), and chronic levodopa therapy 0.77 (95% CI 0.61-0.93). The number of patients positive for each test divided by the number with clinically diagnosed de novo disease was: apomorphine 0.63 (95% CI 0. 56-0.70), acute levodopa 0.69 (95% CI 0.59-0.80), and chronic levodopa therapy 0.76 (95% CI 0.70-0.82). CONCLUSIONS: The accuracy of the acute levodopa and apomorphine challenge tests is similar to, but not superior than, that of chronic levodopa therapy in the diagnosis of idiopathic Parkinson's disease. As most patients will be given chronic dopamimetic therapy, these tests add nothing while causing significant adverse events and additional cost.     

Apomorphine test for dopaminergic responsiveness in patients with previously untreated Parkinson's disease.

We prospectively examined the predictive value of the apomorphine test for the therapeutic efficacy of sustained oral levodopa treatment in 62 patients with de novo Parkinson syndrome (no additional neurological deficit) who had not previously been treated with dopaminergic medication. Patients received 2 to 5 mg of apomorphine hydrochloride subcutaneously and a subsequent trial of oral levodopa of at least 3 months' duration. In three patients, response to apomorphine could not be evaluated owing to side effects experienced during the test. In the remaining 59 patients, the best predictor of response to oral levodopa was the apomorphine-induced relative decrease in the scores on the motor examination part of the Unified Parkinson Disease Rating Scale (UPDRS). At a cutoff value of 20% improvement in UPDRS scores, the test predicted the response to levodopa correctly in 50 patients (85%). The sensitivity of the test was 90%, specificity 88%. The positive predictive value was 95%. However, seven of 19 apomorphine test-negative patients experienced a good (n = 4) or partial (n = 3) improvement with levodopa therapy. Thus, the negative predictive value was only 63%. We conclude that response to apomorphine has a high predictive value for response to sustained oral levodopa treatment in most previously untreated patients, but a negative test should not preclude an adequate trial of oral levodopa.     

Apomorphine in the diagnosis and treatment of parkinsonian tremor

The response of rest tremor to single doses of subcutaneous apomorphine and oral levodopa was compared in 20 patients with tremor-dominant Parkinson's disease. In eight of these patients, who were experiencing refractory levodopa-induced fluctuations characterised by disabling tremor, we studied the efficacy of sustained subcutaneous apomorphine. Nineteen patients responded favourably to acute challenges of both apomorphine and levodopa, with abolition of tremor in 10. In three, the response was helpful in confirming the clinical diagnosis. Chronic apomorphine use led to a more than 50% reduction in tremor-filled hours per day. After a mean duration of follow-up of 7.5 months, there was no tachyphylaxis to its therapeutic action. Subcutaneous apomorphine is an effective adjunct in treating patients with resistant, tremor-dominant fluctuations, and may also be helpful in the diagnosis of parkinsonian tremor.     

Levodopa treatment does not affect low-dose apomorphine test in patients with Parkinson's disease.

Challenge with low-dose apomorphine causes a significant rise in growth hormone (GH) in patients with Parkinson's disease (PD) compared to controls and patients with multiple system atrophy (MSA) who have not previously received dopaminergic treatment. To date, it has not been demonstrated whether an apomorphine-induced rise in GH can still be detected in PD patients who are currently treated with levodopa. We investigated whether an ongoing treatment with levodopa influences the GH response to subcutaneously applied low-dose apomorphine in PD patients. We studied 44 patients with idiopathic PD using the low-dose apomorphine test. Twenty-three patients were under treatment with levodopa and 21 patients were without any dopaminergic therapy. GH and cortisol levels were analyzed at time of injection and 45 minutes and 60 minutes after subcutaneous apomorphine injection. Forty-five minutes after apomorphine injection, there was no significant difference between the mean rise in plasma GH in untreated PD patients compared with levodopa-treated patients (P = 0.235). There was no increase of cortisol levels in each treatment group. Age, sex, duration, and severity of the disease did not show a covariate effect with GH levels. A small group of PD patients (n = 8) treated with dopamine agonists and a small group of patients with MSA (n = 5) as well as patients with vascular parkinsonism (n = 5) did not show any increase of GH. Our data suggest that the apomorphine-induced rise in GH does not depend on previous levodopa treatment in PD patients but, as expected, is blocked by dopamine agonists and is not present in patients with other than idiopathic parkinsonian syndrome. Thus, the low-dose apomorphine test may also be a useful biological marker in the early differential diagnosis of PD patients who have already received levodopa treatment.     

Levodopa dose-related fluctuations in presumed olivopontocerebellar atrophy

The parkinsonism that occurs in some patients with olivopontocerebellar atrophy (OPCA) can cause diagnostic confusion with idiopathic Parkinson's disease (IPD). The response to levodopa is usually a distinguishing feature, the OPCAs either failing to benefit or losing efficacy relatively quickly. A fluctuating response to levodopa in those OPCA patients who do benefit has not been emphasized in the literature previously. Reported here are three patients with presumed OPCA, dominated by parkinsonian features, who eventually developed typical fluctuations with morning akinesia, wearing off, and periodic lack of response related to meals. These fluctuations were a major source of disability and an important reason for diagnostic confusion with IPD. The possible mechanisms of these fluctuations are discussed.     

Affective symptoms in multiple system atrophy and Parkinson's disease: response to levodopa therapy

The objective was to determine the extent to which psychiatric disturbances (especially mood disorders) generally considered poor prognostic factors, are present in patients with striatonigral (SND) type multiple system atrophy (MSA) compared with patients with idiopathic Parkinson's disease (IPD). The Hamilton depression scale (HAM-D), brief psychiatric rating scale (BPRS), and Unified Parkinson's disease rating scale (UPDRS) were administered to clinically probable non-demented patients with SND-type MSA and patients with IPD matched for age and motor disability, at baseline and after receiving levodopa. At baseline total HAM-D score was greater in patients with IPD. Overall, BPRS score did not differ between the two groups; however, patients with IPD scored higher on anxiety items of the BPRS, and patients with MSA had higher scores on the item indicating blunted affect. After levodopa, both groups improved significantly in UPDRS and HAM-D total scores (just significant for patients with MSA). Patients with IPD improved significantly in total BPRS score but patients with MSA did not. At baseline patients with IPD were more depressed and anxious than patients with MSA who, by contrast, showed blunted affect. After levodopa, depression and anxiety of patients with IPD improved significantly whereas the affective detachment of patients with MSA did not change. Major neuronal loss in the caudate and ventral striatum, which are part of the lateral orbitofrontal and limbic circuits, may be responsible for the blunted affect not responsive to levodopa therapy found in patients with MSA.     

Intranasal apomorphine in parkinsonian on-off fluctuations.

The efficacy of intranasal apomorphine was assessed in seven patients with Parkinson's disease and severe levodopa (L-dopa)-related "off-period" disabilities. All patients responded favorably to treatment with intranasal apomorphine. The speed and the quality of motor response and the pharmacokinetic profile showed results similar to those seen after subcutaneous injection of apomorphine administered by insulin pen syringe. The simplicity in the technique of intranasal apomorphine administration was found to be superior by all patients.     

Brain grafting may reverse loss of responsiveness to levodopa therapy in Parkinson's disease

Loss of efficacy and response fluctuations develop in many patients with Parkinson's disease after long-term levodopa therapy. This may be due in part to near-total degeneration of the surviving nigrostriatal dopaminergic neurons during disease progression, with massive decreases in the capacity of the striatum to form and store dopamine from exogenous levodopa. It was recently suggested that intracerebral grafting of fetal nigral or adrenal chromaffin cells may be beneficial in advanced Parkinson's disease by reestablishing spontaneous dopaminergic neurotransmission or by secretion of trophic factors that promote sprouting of residual dopaminergic nerve-terminals. It is now hypothesized that intrastriatal transplantation of such cellular elements that contain the enzyme dopa decarboxylase and dopamine storage sites may significantly increase synthesis, storage, and release of dopamine from exogenous levodopa. It may therefore reverse loss of responsiveness and restore the initial smooth and stable beneficial effect of levodopa therapy.     

Short-term levodopa test assessed by movement time accurately predicts dopaminergic responsiveness in Parkinson's disease

Short-term challenges with dopaminergic agents are used in patients with idiopathic Parkinson's disease (IPD) to predict the therapeutic effect of sustained levodopa treatment, but false-negative results often occur. We prospectively evaluated 74 patients with clinically diagnosed IPD and compared the predictive value of a short-term levodopa test assessed by movement time (MT) with the predictive value obtained by the evaluation with the motor examination part of the Unified Parkinson's Disease Rating Scale (UPDRS-ME). The response to long-term levodopa was accurately predicted in 96% of patients by assessing the response to the short-term test with MT and in 80% of cases with UPDRS-ME. Similar predictive values were obtained by separately analyzing 21 de novo patients. The short-term test also accurately predicted the magnitude of improvement with long-term treatment. We conclude that the predictive value for long-term dopaminergic responsiveness may be further enhanced by evaluating the short-term pharmacologic challenges with MT analysis. This is particularly useful to select de novo patients for drug trials with dopaminergic agents.     

Motor response to apomorphine in patients with Parkinson's disease with long-duration response to levodopa

The authors studied the motor response to apomorphine before and 1 year after levodopa therapy in 12 patients with Parkinson's disease. At the 1-year evaluation, the basal tapping score, recorded after a 12-hour levodopa withdrawal, was higher compared with the test performed while patients were de novo, indicating the presence of a long-duration response to levodopa. The amplitude (net increase) of the motor response to apomorphine was similar before and during levodopa therapy. However, because of the better baseline, the maximal tapping score was higher during levodopa therapy. The duration and the latency of the motor response to apomorphine did not change. The presence of a short-duration response to apomorphine, in the presence of a long-duration response to levodopa, may imply that either different compartment (i.e., postsynaptic versus presynaptic) or transduction pathways are involved in such responses.     

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.     

Patterns of clinical response and plasma dopa levels in Parkinson's disease.

Serial determinations of plasma dihydroxyphenylalanine (dopa) in 16 Parkinson's disease patients receiving levodopa showed a negative correlation between plasma dopa levels and disability scores among patients who exhibited daily fluctuations of signs and symptoms. This suggests that the amount of levodopa delivered to the brain from the periphery is of major importance in the production of the "on-off" phenomenon. A close relationship between plasma dopa levels and abnormal involuntary movements was present in six patients. In three a striking dissociation between control of Parkinson's disease and abnormal involuntary movements was present, suggesting that in some patients these two effects are mediated through different underlying mechanisms. Administration of levodopa in such a way as to prevent both high and low levels of dopa in plasma minimizes disability in Parkinson's disease and may lessen abnormal involuntary movements in patients with the "on-off" effect.     

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.     

Motor response to apomorphine and levodopa in asymmetric Parkinson''s disease.

The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.     

Variation in the dopaminergic response during the day in Parkinson disease

OBJECTIVE: In many parkinsonian patients with fluctuating disease the early morning levodopa dose is more effective than the following dose on the same day. In this study we investigated whether the poor responsiveness to the early afternoon dose of levodopa depends only on peripheral and central levodopa pharmacokinetics or also on pharmacodynamic factors. METHODS: Ten parkinsonian patients experiencing postprandial drug-resistant off periods received two boluses of apomorphine by subcutaneous injection at 8 am and 3 pm on two nonconsecutive days. On day 2, therapy was stopped at 11 am. For each bolus we determined time to on, duration of the on state, magnitude of benefit, and levodopa and apomorphine plasma levels at baseline and immediately after patients reached the on state. RESULTS: The mean duration of on phases was significantly shorter and the apomorphine plasma level needed to reach the on state was significantly higher in the afternoon than in the morning (P<0.01 by paired t test). CONCLUSIONS: This study suggest that there is a change in responsiveness to dopaminergic stimulation during the day. The less effective dopaminergic response in afternoon depends on pharmacodynamic factors and not only on peripheral and central levodopa pharmacokinetic.     

Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson''s disease: implications for the pathogenesis of the on-off phenomenon.

OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine and levodopa. The latency, duration, and magnitude of motor response was measured. RESULTS--A progressive shortening of mean latency after levodopa challenge was found passing from the untreated to the stable and fluctuating groups; the difference between untreated and fluctuating patients was statistically significant (P < 0.01). Response duration after levodopa challenge was similar in untreated and stable patients, whereas it showed a significant shortening in patients with motor fluctuations (P < 0.05 v both untreated and stable patients). When subcutaneous apomorphine was given, untreated patients had a longer response duration than those who had developed motor fluctuations (P < 0.05). Although baseline disability was significantly greater in the fluctuating patients than in the untreated and stable patients, the severity of residual parkinsonian signs after both apomorphine and levodopa challenge was similar for all three groups; as a result, the degree of improvement in parkinsonian signs after dopaminergic stimulation was substantially greater in more advanced than in early cases. Linear regression analysis also indicated that latency and duration after apomorphine challenge did not significantly correlate with those after levodopa challenge, whereas magnitude of response to apomorphine showed a strong positive correlation with that after levodopa challenge (r = 0.9, P < 0.001). CONCLUSION--The progressive shortening of motor response after both apomorphine and levodopa suggests that pharmacodynamic factors play an important part in determining the duration of motor response and argue against altered central pharmacokinetics of levodopa being principally responsible for the on-off effect. The widening response amplitude and increasing off phase disability occurring during disease progression are also critical factors in determining the appearance of motor fluctuations.