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Acute stepwise challenge test with levodopa in treated patients with parkinsonism
Parkinsonism and Related Disorders 15 (2009) 354–358
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Acute stepwise challenge test with levodopa in treated patients with parkinsonism Tao Feng a, *, Wei Li a, Linlong Lu a, Yilong Wang a, Weixiong Shi a, Jianguo Zhang b, Yongjun Wang a, Piu Chan c, ** a b c
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 March 2008 Received in revised form 13 August 2008 Accepted 17 August 2008
Objective: The aim of this study was to establish a new stepwise type of acute challenge test with incremental doses of levodopa/benserazide, and verify its predictive value in follow-up diagnoses and outcomes of deep-brain stimulation (DBS) in treated patients with parkinsonism.
Keywords: Parkinson’s disease Levodopa Stepwise test Parkinsonism
Outcomes: The optimal cutoff points for UPDRS-III improvement in these stepwise levodopa tests. In this study, we established acute challenge tests with incremental doses of levodopa/benserazide (100/25 mg, 150/37.5 mg, 200/50 mg and 300/75 mg) in treated patients with parkinsonism (n ¼ 175). The receiver operating characteristic (ROC) curves were plotted to compare peak UPDRS-III improvement of PD patients (n ¼ 112) with that of non-PD parkinsonism patients (n ¼ 63). The point on the ROC curve with the highest Youden index was defined as the optimal cutoff point in motor improvement for differential diagnoses. The results of the new tests were compared with follow-up diagnoses and the outcomes of DBS. Results: The optimal cutoff points for UPDRS-III improvement with maximal Youden Indices on ROC curves from the tests, with the four incremental doses of levodopa/benserazide, were 12.2% (100/25 mg), 22.3% (150/37.5 mg), 27.9% (200/50 mg) and 33.4% (300/75 mg). The test showed significant correlation with follow-up diagnosis and the outcomes of DBS (P of Kappa <0.01). Conclusions: The results suggested that the new acute stepwise levodopa challenge test is a useful tool for the diagnosis of PD. Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Design: Prospective cohort study.
1. Introduction The clinical diagnosis of Parkinson’s disease (PD) is difficult due to the lack of specific biomarkers [1]. Other forms of parkinsonism may present with clinical features that overlap with PD, and a high frequency of diagnostic errors has been reported in clinical pathological studies [2–6]. Dopaminergic responsiveness has been proposed as a key prospective supporting feature in established clinical criteria for PD and for the prediction of response to chronic
* Corresponding author. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 6, Tiantan Xili, Chongwen District, Beijing 100050, China. Tel.: þ86 10 67098343; fax: þ86 10 67098350. ** Corresponding author. Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Xuanwu District, Beijing 100053, China. Tel.: þ86 10 83198677; fax: þ86 10 83161294. E-mail addresses: [email protected], [email protected] (T. Feng), pbchan@ bjsap.org (P. Chan).
treatment [7]. Challenge tests with a dopaminergic drug, used to assess dopaminergic responsiveness, include acute challenge with levodopa, chronic challenge with levodopa and acute challenge with apomorphine. Acute challenge with levodopa may represent the most convenient compromise between sensitivity and specificity among these tests [8–15]. In previous studies, only a single dose of levodopa was used to perform the acute challenge test [10–15], which could only partly evaluate levodopa responsiveness because the motor response varies with different doses of levodopa [16]. Although the motor response changes with time after the administration of levodopa [17], with one exception [18] motor status was evaluated at a single fixed time rather than continuously [10–15]. Apart from these similarities, there was considerable methodological variation, particularly the assessment methods and the thresholds used to define a positive response [9–15]. The motor responses were assessed by means of clinical scales (for example, modified Webster score, tremor score [11], and Unified Parkinson’s Disease Rating
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T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
Scale subset III (UPDRS-III) score [14,15]), clinical measures (finger tapping speed, walking time [11–13]), or instrumental measurement [19]. The criteria for a positive response to acute levodopa challenge were always established a priori [10–13]. The receiver operating characteristic (ROC) curves were plotted to achieve the best balance between sensitivity and specificity; however, the criteria for selecting the optimal cutoff point for motor improvement on ROC curves was still empirical [14,15]. PD itself and treatment also influence levodopa responsiveness, apart from the methodology of the test. The major determinant of motor responses to levodopa is the degree of dopamine depletion [20]. Levodopa availability changes with the progression of PD probably due to alterations in its pharmacokinetics [21]. Previously untreated PD patients and treated PD patients show different dopaminergic responsiveness, indicating an effect of long term treatment with replacement medications [18]. The aim of the present prospective cohort study was to establish a new stepwise type of acute challenge test with incremental doses of levodopa/benserazide, and to verify its predictive value in follow-up diagnoses and outcomes of deep-brain stimulation (DBS) in treated patients with parkinsonism. The ROC curves comparing the motor responses of treated PD patients to those of treated patients with non-PD parkinsonism were plotted based on peak improvement in motor score (UPDRS-III) [22]. The point on the ROC curve with the highest Youden index (YI) was defined as the optimal cutoff point in motor improvement for differential diagnoses. The results of the new tests were compared with follow-up diagnoses and the outcomes of DBS.
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t.i.d.), starting 24 h before the tests. Levodopa challenge tests were performed in the morning following overnight fasting and withdrawal of all antiparkinsonian medication for 12 h, in accordance with published guidelines [24]. An initial test was performed with 100/25 mg of levodopa/benserazide on the first day. Repeated levodopa/benserazide challenge tests with stepwise incremental doses of 150/ 37.5 mg, 200/50 mg and 300/75 mg were performed on the following three days. The dose of levodopa/benserazide was increased until either side effects occurred or the maximal dose was reached. Two raters blind to the selection of patients and administration of levodopa/benserazide assessed the motor response. Motor response was evaluated by clinical rating according to the UPDRS-III [22] at baseline, immediately before administration of levodopa/benserazide and at 15-min intervals to 4 h following administration. The average percentage of peak UPDRS-III improvement compared with baseline was defined as the motor response to levodopa.
2.3. Follow-up of clinical diagnosis and outcomes of DBS Of the 175 patients who completed acute stepwise challenge tests, 167 patients (108 patients with PD, 59 patients with non-PD parkinsonism) were followed up by a movement disorders neurologist who was blind to the selection of subjects and levodopa tests. The follow-up diagnosis was updated according to UKPDSBB PD criteria and patients were categorized as having PD or non-PD parkinsonism at 24 months after the challenge tests. The Core Assessment Program for Surgical Interventions and Transplantation in Parkinson’s Disease (CAPSIT-PD) was adopted to identify potential candidates for DBS [24,25]. Sixty-five of the patients who completed the challenge tests underwent bilateral DBS of the subthalamic nucleus (STN, n ¼ 42) or globus pallidus internus (GPi, n ¼ 23). Sixty-three patients who underwent DBS were followed for two years. A combination of DBS programming and antiparkinsonian medication adjustment was used to achieve optimal outcomes of DBS. The DBS electrodes were adjusted when misplacement was identified by MR imaging. At 24 months post-operation, the clinical improvement without antiparkinsonian drugs and the stimulator on was compared with the stimulator off. The criterion for the efficacy of DBS was >30% improvement in UPDRS-III at the time of maximal clinical improvement.
2. Patients and methods 2.4. Statistical analysis 2.1. Subjects From February of 2004 to November of 2005 one hundred and eighty-two patients with parkinsonian symptoms referred to the movement disorders section of Beijing Tiantan Hospital were selected consecutively to perform an acute challenge test. These patients satisfied step one of the United Kingdom Parkinson’s Disease Society brain bank (UKPDSBB) diagnostic criteria for PD [23], and were diagnosed as having parkinsonism. Among these patients, 117 patients who satisfied steps 2 and 3 of the UKPDSBB criteria were diagnosed as having PD (PD group); the other 65 patients were diagnosed as having non-PD Parkinsonism (non-PD group). The enrolled patients also fulfilled the following criteria: (1) being treated with levodopa or having been treated with levodopa; (2) no sign of other neurological diseases on cerebral MRI/CT scan; (3) no history of other neurological and psychiatric diseases; and (4) not taking medications with central nervous system action. One hundred and seventy-five patients completed the acute stepwise challenge tests with four doses of levodopa; seven patients withdrew from the study due to side effects. Of the 175 patients who completed the tests, 112 patients were diagnosed as having PD and 63 patients were patients with non-PD parkinsonism, including nine with possible multiple system atrophy (MSA), 12 with probable MSA, six with progressive supranuclear palsy (PSP), three with corticobasal degeneration, seven with vascular parkinsonism, and 26 with non-classified parkinsonism. The demographics and clinical characteristics of patients who completed the tests are presented in Table 1. The study was approved by the local ethics committee and informed written consent was obtained from each patient. 2.2. Acute stepwise challenge tests with levodopa/benserazide An examiner who was blind to the selection of subjects, performed acute stepwise challenge tests with levodopa/benserazide. In order to prevent side effects, all patients received the peripheral dopamine antagonist domperidone (10 mg,
Statistical analyses were performed using SPSS for Windows 11.5. Student’s ttests were used to compare differences in normally distributed data between the PD group and the non-PD group. The Mann–Whitney test was used to compare differences between the two groups when the data was not normally distributed. ROC curves were plotted comparing the peak UPDRS-III improvement of PD patients to that of patients with non-PD parkinsonism. The ability of the tests to discriminate patients with PD from those with non-PD parkinsonism was shown by the sensitivity and specificity of a range of arbitrarily chosen cutoff points on the ROC curves. The point on the ROC curve with the maximal Youden Index (YI, YI ¼ sensitivity þ specificity1) [26] was defined as the optimal cutoff point for UPDRS-III improvement. The tests were regarded as positive when patients showed higher peak improvement of UPDRS-III than the cutoff points. Comparisons of categorical variables were made using the Chi-square test. The sensitivity, specificity, positive prediction value (PPV), negative prediction value (NPV), Youden index and overall accuracy of prediction of the follow-up diagnosis or the outcomes of DBS were calculated. The consistency between the results of the tests and follow-up diagnosis, or between the results of the tests and the outcomes of DBS, were evaluated on the basis of Kappa values. The sensitivity and specificity of predicting follow-up diagnoses in any two of the four challenges were compared by Bennett’s method [27]. The significant level was set at P < 0.05.
3. Results There were no significant differences in mean age, gender, duration of symptoms, Hoehn–Yahr stage and UPDRS-III scores between the PD group and the non-PD group at baseline (P < 0.01, Table 1).
Table 1 Characteristics of subjects who completed tests with the four doses of levodopa
Age (year, mean SD) Gender (M/F) Duration of symptoms (year, mean SD) H–Y stage ‘‘off’’ (mean SD) UPDRS-III ‘‘off’’ (mean SD)
PD group (n ¼ 112)
Non-PD group (n ¼ 63)
P *value
61.7 11.3 70/42 5.5 5.1 2.25 1.03 32.2 18.0
60.1 10.9 38/25 4.3 3.6 2.37 1.25 29.8 16.6
0.344 0.839 0.110 0.271 0.487
* P > 0.05, PD vs. non-PD parkinsonism. UPDRS, unified Parkinson’s disease rating scale.
T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
The average UPDRS-III improvement of the PD group was significantly higher than that of the non-PD group in tests with all four doses of levodopa/benserazide (P < 0.001, Table 2). Fig. 1 shows the four ROC curves from the tests. The area under the curve (AUC) of ROC curves from the tests with levodopa/benserazide was 0.834 (100/25 mg), 0.864 (150/37.5 mg), 0.903 (200/ 50 mg), and 0.913 (300/75 mg). These curves displayed statistical difference for differential diagnoses between patients with PD and those with non-PD parkinsonism (P < 0.001). When patients with PD were compared with patients with nonPD parkinsonism, the maximal Youden Indices that optimal cutoff points for UPDRS-III improvement on ROC curves could yield, in tests with the four incremental doses of levodopa/benserazide, were 0.592 (100/25 mg), 0.650 (150/37.5 mg), 0.722 (200/50 mg) and 0.715 (300/75 mg). The optimal cutoff points that achieved the best diagnostic accuracy were 12.2% (levodopa/benserazide 100/ 25 mg, sensitivity 80.2%, specificity 79%), 22.3% (150/37.5 mg, sensitivity 81.1%, specificity 83.9%), 27.9% (200/50 mg, sensitivity 88.3%, specificity 83.9%), and 33.4% (300/75 mg, sensitivity 89.2%, specificity 82.3%) (Table 3). The results of the tests showed significant consistency with the follow-up diagnoses at 24 months, with Kappa values of 0.504 (100/ 25 mg), 0.666 (150/37.5 mg), 0.694 (200/50 mg) and 0.678 (300/ 75 mg), for the four incremental doses of levodopa/benserazide (P < 0.01). At 24 months, the test with 300/75 mg of levodopa/ benserazide yielded the highest sensitivity of 89.7% and the highest NPV of 81.4%, while the test with 150/37.5 mg of levodopa/benserazide yielded the highest specificity of 85.5% and the highest PPV of 90.8%. The test with 100/25 mg of levodopa/benserazide to predict follow-up diagnosis was significantly lower in terms of sensitivity than tests with 200/50 mg or 300/75 mg of levodopa/ benserazide (P < 0.01), and significantly lower in terms of specificity than the test with 150/37.5 mg of levodopa/benserazide (P < 0.05). There was no significant difference in sensitivity or specificity between tests with any other two of the four doses (P > 0.05) (Table 4). The results of tests with 150/37.5 mg, 200/50 mg and 300/75 mg of levodopa/benserazide showed significant correlation with the outcomes of DBS (Kappa values of 0.373, 0.642 and 0.849; P < 0.01) with the exception of the test with 100/25 mg of levodopa/benserazide (Kappa ¼ 0.126, P ¼ 0.187). The PPV and NPV increased synchronously with levodopa dose. The NPVs of the tests with 100/ 25 mg and 150/37.5 mg of levodopa/benserazide were only 13.3% and 30.0%, although the PPVs were 96.0% and 98.2%. The test with 300/75 mg of levodopa/benserazide yielded a PPV of 98.4% and an NPV of 100% (Table 5). 4. Discussion Our study has established a new method of acute stepwise challenge test with incremental doses of levodopa and continuous assessment of UPDRS-III at short intervals. The strengths of our study are: First, the motor response to incremental doses of levodopa was evaluated in 175 parkinsonian patients. Second, the ROC curves of acute stepwise tests with four doses of levodopa/
ROC Curve
1.00
.75
Sensitivity
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Source of the Curve .50
Reference Line D375MG D250MG
.25
D187.5MG D125MG 0.00 0.00
.25
.50
.75
1.00
1- Specificity Diagonal segments are produced by ties. Fig. 1. ROC curves from the acute stepwise challenge tests with four doses of levodopa/ benserazide (n ¼ 175). Red line: ROC curve of test with 100/25 mg of levodopa/benserazide (AUC ¼ 0.834, P < 0.001); Green line: ROC curve of test with 150/37.5 mg of levodopa/benserazide (AUC ¼ 0.864, P < 0.001); Blue line: ROC curve of test with 200/ 50 mg of levodopa/benserazide (AUC ¼ 0.903, P < 0.001); Purple line: ROC curve of test with 300/75 mg of levodopa/benserazide (AUC ¼ 0.913, P < 0.001). ROC, receiver operating characteristic; AUC, area under curve.
benserazide all displayed statistical difference. Third, the results of the acute stepwise tests were not only compared with follow-up diagnoses of 167 subjects, but also compared with the outcome of DBS in 63 subjects 24 months later. The critical index of a diagnostic test is the optimal cutoff point [26]. The present study showed that the optimal cutoff points for UPDRS-III improvement in challenge tests with the four incremental doses of levodopa/benserazide were 12.2% (100/25 mg), 22.3% (150/37.5 mg), 27.9% (200/50 mg) and 33.4% (300/75 mg). The discrepancies between these optimal cutoff points and those of previous studies were not only because of the different doses of levodopa used in the tests, but also due to the different methods for identifying the cutoff points. Merello et al. [15] rated the test with 250/50 mg of levodopa/carbidopa as positive or negative according to whether values reached a minimal 30% of improvement on UPDRS-III; however, Zappia et al. [13] used with the same dose of drug, but defined a result as positive when improvement on UPDRS-III was >20%. Rossi et al. [14] defined the point on the ROC curve closest to 80% sensitivity and 80% specificity as the optimal cutoff point for UPDRS-III. In the present study the ROC curves were also plotted based on the motor improvement of the two groups, with the AUC of ROCs having significant statistical difference. This suggested that the stepwise tests had discriminating ability, and it was possible to find optimal cutoff points on ROC curves for
Table 2 Improvement in UPDRS-III scores in the two groups Levodopa/benserazide
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
PD group (n ¼ 112)
Non-PD group (n ¼ 63)
Mean SD
95%CI
18.72% 8.89% 29.97% 11.54% 40.36% 13.19% 49.93% 15.32%
17.05%, 20.40% 27.80%, 32.14% 37.88%, 42.85% 47.05%, 52.81%
Mean SD
P value Median
95%CI
6.78%* 11.50%* 18.48 11.14% 22.67% 12.45%
15.65%, 21.31% 19.51%, 25.83%
* Non-normally distributed data. ** PD vs. non-PD, with Mann–Whitney test. *** PD vs. non-PD, with Student’s t-test. CI, confidence interval.
<0.001** <0.001** <0.001*** <0.001***
T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
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Table 3 Optimal cutoff values of UPDRS-III improvement in levodopa tests (n ¼ 175) Levodopa/benserazide
Maximal Youden index*
Optimal cutoff values
Sensitivity
Specificity
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
0.592 0.650 0.722 0.715
12.2% 22.3% 27.9% 33.4%
80.2% 81.1% 88.3% 89.2%
79% 83.9% 83.9% 82.3%
* Youden index ¼ sensitivity þ specificity1.
differential diagnoses. Then, the cutoff point on the ROC curve with the maximal value of Youden index was defined as the optimal cutoff value with the best balance of sensitivity and specificity [26]. The predictive accuracy of the optimal cutoff points in the stepwise tests was assessed by follow-up over two years. The follow-up diagnoses were also made according to the UKPDSBB criteria for PD, which have the highest clinical diagnostic accuracy. These criteria for the diagnosis of PD have an estimated diagnostic specificity of 98.6% and sensitivity of 91.1% [28]. The present study shows that the results of acute stepwise challenge tests with levodopa/benserazide have significant correlation with the followup diagnosis 24 months later. As follow-up diagnosis was not a definite standard for evaluating the tests, verification by other means should also be performed. As DBS provides significant benefit to PD patients, but not patients with non-PD parkinsonism [24,25], the efficacy of DBS is a supportive item for the diagnosis of PD rather than non-PD parkinsonism. Thus, the correlation between acute challenge tests and the outcomes of DBS suggests that positive results of the tests may also predict a diagnosis of PD rather than non-PD parkinsonism. DBS can significantly improve the UPDRS-III of PD (43% at 1 year [29], 37.2% at 3 years and 35.1% at 5 years [30]), and the indication for DBS is >30% improvement in UPDRS-III score [24,25]. Thus, the outcomes of DBS were rated as effective when the improvement in UPDRS-III score was higher than 30% in the present study. The results showed that tests with 150/37.5 mg, 200/50 mg and 300/75 mg of levodopa/benserazide had statistically significant correlation with the outcomes of DBS, with the exception of the test with 100/25 mg of levodopa/benserazide. These findings provide indirect evidence that positive results in the stepwise tests may predict a diagnosis PD. The test with 100/25 mg of levodopa/benserazide was significantly lower in sensitivity to predictive follow-up diagnoses than the tests with 200/50 mg and 300/75 mg respectively, and was also significantly lower in specificity than the test with 150/37.5 mg. However there was no significant difference in sensitivity or specificity between tests with any other two of the four doses. These results indicated that any one of 150/37.5 mg, 200/50 mg or 300/75 mg of levodopa/benserazide could be used to perform an acute challenge for differential diagnoses, because of their similar sensitivity and specificity. The test with 300/75 mg of levodopa/ benserazide yielded a PPV of 98.4% and an NPV of 100% to predict the efficacy of DBS, while the NPVs of the tests with 150/37.5 mg and 200/50 mg were only 30.0% and 60.0%. These results indicated that an acute challenge test with 300/75 mg of levodopa/benserazide, rather than the other three doses, should be used as screening tool to identify potential candidates for DBS.
The diagnostic sensitivities of the optimal cutoff points in these stepwise tests ranged from 80.2% to 89.2%, and the corresponding diagnostic specificities ranged from 79% to 83.9%. In a meta-analysis review, the 95%CI of sensitivity of acute levodopa challenge for the diagnosis of established PD was between 0.64 and 0.85, while the specificity was between 0.59 and 0.80 [8]. Rossi et al. [14] showed that the levodopa test yielded a sensitivity of 77.1% and a specificity of 71.1% for differential diagnosis of parkinsonism. Merello et al. [15] reported that the overall sensitivity and specificity of acute levodopa challenge to predict clinical diagnosis of PD were 70.9% and 81.4% respectively. These results suggested that the diagnostic sensitivity and specificity achieved in the present study were superior to those achieved in previous studies. However, direct statistical comparison of predictive values between the present study and previous studies could not be made due to the heterogeneous methodologies used. Some factors that may influence the dopaminergic response should be taken into account when interpreting the results of the challenge tests with levodopa. Previously treated PD patients and never treated patients may show different levodopa responsiveness [18]; meanwhile, most patients with parkinsonism referred to undergo acute challenge tests are those without definite responsiveness after being treated with levodopa. In the present study, the enrolled subjects were all being treated for parkinsonism. Because the subjects varied in their protocol of levodopa substitution, including the duration of substitution, the dose of levodopa, and adjunctive treatment with dopamine receptor agonist, we could not compare the two groups based on matched-substitution of levodopa. The response to levodopa changes during the course of PD [20]. Nutt et al. showed that the magnitude of the response was significantly greater in more advanced stages [31]. In the present study, there was no statistical difference in the duration of motor symptoms, H–Y stage and UPDRS-III scores between the two groups, so the comparison of levodopa responsiveness between the two groups could be interpreted on the equivalent severities of movement disturbance. Parkinsonisms are clinicopathological entities, for which a definite diagnosis can only be established by autopsy [1]. In this study, the diagnosis used as standard was based on clinical criteria, and the length of follow-up was not comparable to the average survival time of patients with other forms of parkinsonism, including MSA and PSP [14,32]. There was no placebo used in the present study, because some of the typical side effects of levodopa (for example, mild nausea) could easily be identified by patients or doctors. Instrumental measurement [19], neurophysiological parameters and functional neuroimaging [9] should be employed for specific
Table 4 Ability of acute stepwise levodopa test to predict follow-up diagnosis 24 months later (n ¼ 167) Levodopa/benserazide
Sensitivity
Specificity
Youden index
Positive predictive value
Negative predictive value
Overall accuracy
Kappa value
P value of Kappa
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
77.6%* 83.2% 88.8%* 89.7%*
74.2%** 85.5%** 80.6% 77.4%
0.518 0.687 0.694 0.671
83.8% 90.8% 88.8% 87.3%
65.7% 74.6% 80.6% 81.4%
76.3% 84.1% 85.8% 85.2%
0.504 0.666 0.694 0.678
<0.01 <0.01 <0.01 <0.01
* Sensitivity: 100/25 mg vs. 200/50 mg. 100/25 mg vs. 300/75 mg, P<0.01. ** Specificity: 100/25 mg vs. 150/37.5 mg, P<0.05.
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T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
Table 5 Ability of acute stepwise levodopa tests to predict the outcomes of DBS 24 months later (n ¼ 63) Levodopa dosage
Sensitivity
Specificity
Youden index
Positive predictive value
Negative predictive value
Overall accuracy
Kappa value
P value of Kappa
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
78.7% 88.5% 96.7% 100%
50.0% 75.0% 75.0% 75.0%
0.287 0.635 0.717 0.750
96.0% 98.2% 98.3% 98.4%
13.3% 30.0% 60.0% 100%
76.9% 87.7% 95.4% 98.4%
0.126 0.373 0.642 0.849
0.187 <0.01 <0.01 <0.01
DBS, deep-brain stimulation.
assessments, although UPDRS-III could assess motor condition comprehensively [22]. In conclusion, we have established new acute stepwise levodopa challenge tests with relatively high predictive accuracy. The new tests might provide a useful additional tool for the clinical diagnosis of PD and for screening appropriate candidates for DBS. Acknowledgements This work was supported by Beijing Tiantan Hospital, Capital Medical University. References [1] Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 2006;5:75–6. [2] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatr 1992;55:181–4. [3] Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:33–9. [4] Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 2001;57:1497–9. [5] Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 1992;42:1142–6. [6] Litvan I, Bhatia KP, Burn DJ, Goetz CG, Lang AE, McKeith I, et al. Movement disorders society scientific issues committee report: SIC task force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18:467–86. [7] Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2006;66:968–75. [8] Clarke CE, Davies P. Systematic review of acute levodopa and apomorphine challenge tests in the diagnosis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 2000;69:590–4. [9] Albanese A, Bonuccelli U, Brefel C, Chaudhuri KR, Colosimo C, Eichhorn T, et al. Consensus statement on the role of acute dopaminergic challenge in Parkinson’s disease. Move Disord 2001;16:197–201. [10] Esteguy M, Bonnet AM, Kefalos J, Lhermitte F, Agid Y. The L-dopa test in Parkinson’s disease. Rev Neurol (Paris) 1985;141:413–5. [11] Hughes AJ, Lees AJ, Stern GM. Challenge tests to predict the dopaminergic response in untreated Parkinson’s disease. Neurology 1991;41:1723–5. [12] D’Costa DF, Sheehan LJ, Phillips PA, Moore-Smith B. The levodopa test in Parkinson’s disease. Age Ageing 1995;24:210–2. [13] Zappia M, Montesanti R, Colao R, Branca D, Nicoletti G, Aguglia U, et al. Shortterm levodopa test assessed by movement time accurately predicts dopaminergic responsiveness in Parkinson’s disease. Move Disord 1997;12:103–6.
[14] Rossi P, Colossi C, Moro E, Tonali P, Albanese A. Acute challenge with apomorphine and levodopa in parkinsonism. Eur Neurol 2000;43:95–101. [15] Merello M, Nouzeilles MI, Arce GP, Leiguarda R. Accuracy of acute levodopa challenge for clinical prediction of sustained long-term levodopa response as a major criterion for idiopathic Parkinson’s disease diagnosis. Move Disord 2002;17:795–8. [16] Nyholm D, Lennernas H, Gomes-Trolin C, Aquilonius SM. Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson’s disease on individual drug combinations. Clin Neuropharmacol 2002;25:89–96. [17] Olanow CW, Schapira AHV, Rascol O. Continuous dopamine-receptor stimulation in the early treatment of Parkinson’s disease. Trends Neurosci 2000;23:S117–26. [18] Muller T, Benz S, Bornke C, Russ H, Przuntek H. Repeated rating improves value of diagnostic dopaminergic challenge tests in Parkinson’s disease. J Neural Transm 2003;110:603–9. [19] Mu¨ller T, Benz S. Quantification of the dopaminergic response in Parkinson’s disease. Parkinsonism Relat Disord 2002;8:181–6. [20] Obeso JA, Rodriguez-Oroz M, Marin C, Alonso F, Zamarbide I, Lanciego JL, et al. The origin of motor fluctuations in Parkinson’s disease: importance of dopaminergic innervation and basal ganglia circuits. Neurology 2004;62:S17–30. [21] Woitalla D, Goetze O, Kim JI, Nikodem AB, Schmidt WE, Przuntek H, et al. Levodopa availability improves with progression of Parkinson’s disease. J Neurol 2006;253:1221–6. [22] Fahn S, Elton RL, members of the UPDRS development committee. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden M, Goldstein M, Calne DB, editors. Recent developments in Parkinson’s disease, vol. 2. New York: Macmillan Healthcare Information; 1987. p. 153–63. [23] Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:745–52. [24] Defer GL, Widner H, Marie´ RM, Re´my P, Levivier M. Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Move Disord 1999;14:572–84. [25] Lang AE, Widner H. Deep brain stimulation for Parkinson’s disease: patient selection and evaluation. Move Disord 2002;17:S94–101. [26] Fluss R, Faraggi D, Reiser B. Estimation of the Youden index and its associated cutoff point. Biom J 2005;47:458–72. [27] Bennett BM. On comparisons of sensitivity, specificity and predictive value of a number of diagnostic procedures. Biometrics 1972;28:793–800. [28] Hughes AJ, Daniel SE, Ben Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125:861–70. [29] Tir M, Devos D, Blond S, Touzet G, Reyns N, Duhamel A, et al. Exhaustive, oneyear follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients. Neurosurgery 2007;61:297– 304. [30] Piboolnurak P, Lang AE, Lozano AM, Miyasaki JM, Saint-Cyr JA, Poon YY, et al. Levodopa response in long-term bilateral subthalamic stimulation for Parkinson’s disease. Move Disord 2007;22:990–7. [31] Nutt JG. Effect of long-term therapy on the pharmacodynamics of Ldopa: relation to on-off phenomenon. Arch Neurol 1992;49:1123–30. [32] Albanese A, Colosimo C, Bentivoglio AR, Fenici R, Melillo G, Tonali P. Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria. J Neurol Neurosurg Psychiatr 1995;59:144–51.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Acute stepwise challenge test with levodopa in treated patients with parkinsonism Tao Feng a, *, Wei Li a, Linlong Lu a, Yilong Wang a, Weixiong Shi a, Jianguo Zhang b, Yongjun Wang a, Piu Chan c, ** a b c
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 March 2008 Received in revised form 13 August 2008 Accepted 17 August 2008
Objective: The aim of this study was to establish a new stepwise type of acute challenge test with incremental doses of levodopa/benserazide, and verify its predictive value in follow-up diagnoses and outcomes of deep-brain stimulation (DBS) in treated patients with parkinsonism.
Keywords: Parkinson’s disease Levodopa Stepwise test Parkinsonism
Outcomes: The optimal cutoff points for UPDRS-III improvement in these stepwise levodopa tests. In this study, we established acute challenge tests with incremental doses of levodopa/benserazide (100/25 mg, 150/37.5 mg, 200/50 mg and 300/75 mg) in treated patients with parkinsonism (n ¼ 175). The receiver operating characteristic (ROC) curves were plotted to compare peak UPDRS-III improvement of PD patients (n ¼ 112) with that of non-PD parkinsonism patients (n ¼ 63). The point on the ROC curve with the highest Youden index was defined as the optimal cutoff point in motor improvement for differential diagnoses. The results of the new tests were compared with follow-up diagnoses and the outcomes of DBS. Results: The optimal cutoff points for UPDRS-III improvement with maximal Youden Indices on ROC curves from the tests, with the four incremental doses of levodopa/benserazide, were 12.2% (100/25 mg), 22.3% (150/37.5 mg), 27.9% (200/50 mg) and 33.4% (300/75 mg). The test showed significant correlation with follow-up diagnosis and the outcomes of DBS (P of Kappa <0.01). Conclusions: The results suggested that the new acute stepwise levodopa challenge test is a useful tool for the diagnosis of PD. Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Design: Prospective cohort study.
1. Introduction The clinical diagnosis of Parkinson’s disease (PD) is difficult due to the lack of specific biomarkers [1]. Other forms of parkinsonism may present with clinical features that overlap with PD, and a high frequency of diagnostic errors has been reported in clinical pathological studies [2–6]. Dopaminergic responsiveness has been proposed as a key prospective supporting feature in established clinical criteria for PD and for the prediction of response to chronic
* Corresponding author. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 6, Tiantan Xili, Chongwen District, Beijing 100050, China. Tel.: þ86 10 67098343; fax: þ86 10 67098350. ** Corresponding author. Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Xuanwu District, Beijing 100053, China. Tel.: þ86 10 83198677; fax: þ86 10 83161294. E-mail addresses: [email protected], [email protected] (T. Feng), pbchan@ bjsap.org (P. Chan).
treatment [7]. Challenge tests with a dopaminergic drug, used to assess dopaminergic responsiveness, include acute challenge with levodopa, chronic challenge with levodopa and acute challenge with apomorphine. Acute challenge with levodopa may represent the most convenient compromise between sensitivity and specificity among these tests [8–15]. In previous studies, only a single dose of levodopa was used to perform the acute challenge test [10–15], which could only partly evaluate levodopa responsiveness because the motor response varies with different doses of levodopa [16]. Although the motor response changes with time after the administration of levodopa [17], with one exception [18] motor status was evaluated at a single fixed time rather than continuously [10–15]. Apart from these similarities, there was considerable methodological variation, particularly the assessment methods and the thresholds used to define a positive response [9–15]. The motor responses were assessed by means of clinical scales (for example, modified Webster score, tremor score [11], and Unified Parkinson’s Disease Rating
1353-8020/$ – see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2008.08.010
T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
Scale subset III (UPDRS-III) score [14,15]), clinical measures (finger tapping speed, walking time [11–13]), or instrumental measurement [19]. The criteria for a positive response to acute levodopa challenge were always established a priori [10–13]. The receiver operating characteristic (ROC) curves were plotted to achieve the best balance between sensitivity and specificity; however, the criteria for selecting the optimal cutoff point for motor improvement on ROC curves was still empirical [14,15]. PD itself and treatment also influence levodopa responsiveness, apart from the methodology of the test. The major determinant of motor responses to levodopa is the degree of dopamine depletion [20]. Levodopa availability changes with the progression of PD probably due to alterations in its pharmacokinetics [21]. Previously untreated PD patients and treated PD patients show different dopaminergic responsiveness, indicating an effect of long term treatment with replacement medications [18]. The aim of the present prospective cohort study was to establish a new stepwise type of acute challenge test with incremental doses of levodopa/benserazide, and to verify its predictive value in follow-up diagnoses and outcomes of deep-brain stimulation (DBS) in treated patients with parkinsonism. The ROC curves comparing the motor responses of treated PD patients to those of treated patients with non-PD parkinsonism were plotted based on peak improvement in motor score (UPDRS-III) [22]. The point on the ROC curve with the highest Youden index (YI) was defined as the optimal cutoff point in motor improvement for differential diagnoses. The results of the new tests were compared with follow-up diagnoses and the outcomes of DBS.
355
t.i.d.), starting 24 h before the tests. Levodopa challenge tests were performed in the morning following overnight fasting and withdrawal of all antiparkinsonian medication for 12 h, in accordance with published guidelines [24]. An initial test was performed with 100/25 mg of levodopa/benserazide on the first day. Repeated levodopa/benserazide challenge tests with stepwise incremental doses of 150/ 37.5 mg, 200/50 mg and 300/75 mg were performed on the following three days. The dose of levodopa/benserazide was increased until either side effects occurred or the maximal dose was reached. Two raters blind to the selection of patients and administration of levodopa/benserazide assessed the motor response. Motor response was evaluated by clinical rating according to the UPDRS-III [22] at baseline, immediately before administration of levodopa/benserazide and at 15-min intervals to 4 h following administration. The average percentage of peak UPDRS-III improvement compared with baseline was defined as the motor response to levodopa.
2.3. Follow-up of clinical diagnosis and outcomes of DBS Of the 175 patients who completed acute stepwise challenge tests, 167 patients (108 patients with PD, 59 patients with non-PD parkinsonism) were followed up by a movement disorders neurologist who was blind to the selection of subjects and levodopa tests. The follow-up diagnosis was updated according to UKPDSBB PD criteria and patients were categorized as having PD or non-PD parkinsonism at 24 months after the challenge tests. The Core Assessment Program for Surgical Interventions and Transplantation in Parkinson’s Disease (CAPSIT-PD) was adopted to identify potential candidates for DBS [24,25]. Sixty-five of the patients who completed the challenge tests underwent bilateral DBS of the subthalamic nucleus (STN, n ¼ 42) or globus pallidus internus (GPi, n ¼ 23). Sixty-three patients who underwent DBS were followed for two years. A combination of DBS programming and antiparkinsonian medication adjustment was used to achieve optimal outcomes of DBS. The DBS electrodes were adjusted when misplacement was identified by MR imaging. At 24 months post-operation, the clinical improvement without antiparkinsonian drugs and the stimulator on was compared with the stimulator off. The criterion for the efficacy of DBS was >30% improvement in UPDRS-III at the time of maximal clinical improvement.
2. Patients and methods 2.4. Statistical analysis 2.1. Subjects From February of 2004 to November of 2005 one hundred and eighty-two patients with parkinsonian symptoms referred to the movement disorders section of Beijing Tiantan Hospital were selected consecutively to perform an acute challenge test. These patients satisfied step one of the United Kingdom Parkinson’s Disease Society brain bank (UKPDSBB) diagnostic criteria for PD [23], and were diagnosed as having parkinsonism. Among these patients, 117 patients who satisfied steps 2 and 3 of the UKPDSBB criteria were diagnosed as having PD (PD group); the other 65 patients were diagnosed as having non-PD Parkinsonism (non-PD group). The enrolled patients also fulfilled the following criteria: (1) being treated with levodopa or having been treated with levodopa; (2) no sign of other neurological diseases on cerebral MRI/CT scan; (3) no history of other neurological and psychiatric diseases; and (4) not taking medications with central nervous system action. One hundred and seventy-five patients completed the acute stepwise challenge tests with four doses of levodopa; seven patients withdrew from the study due to side effects. Of the 175 patients who completed the tests, 112 patients were diagnosed as having PD and 63 patients were patients with non-PD parkinsonism, including nine with possible multiple system atrophy (MSA), 12 with probable MSA, six with progressive supranuclear palsy (PSP), three with corticobasal degeneration, seven with vascular parkinsonism, and 26 with non-classified parkinsonism. The demographics and clinical characteristics of patients who completed the tests are presented in Table 1. The study was approved by the local ethics committee and informed written consent was obtained from each patient. 2.2. Acute stepwise challenge tests with levodopa/benserazide An examiner who was blind to the selection of subjects, performed acute stepwise challenge tests with levodopa/benserazide. In order to prevent side effects, all patients received the peripheral dopamine antagonist domperidone (10 mg,
Statistical analyses were performed using SPSS for Windows 11.5. Student’s ttests were used to compare differences in normally distributed data between the PD group and the non-PD group. The Mann–Whitney test was used to compare differences between the two groups when the data was not normally distributed. ROC curves were plotted comparing the peak UPDRS-III improvement of PD patients to that of patients with non-PD parkinsonism. The ability of the tests to discriminate patients with PD from those with non-PD parkinsonism was shown by the sensitivity and specificity of a range of arbitrarily chosen cutoff points on the ROC curves. The point on the ROC curve with the maximal Youden Index (YI, YI ¼ sensitivity þ specificity1) [26] was defined as the optimal cutoff point for UPDRS-III improvement. The tests were regarded as positive when patients showed higher peak improvement of UPDRS-III than the cutoff points. Comparisons of categorical variables were made using the Chi-square test. The sensitivity, specificity, positive prediction value (PPV), negative prediction value (NPV), Youden index and overall accuracy of prediction of the follow-up diagnosis or the outcomes of DBS were calculated. The consistency between the results of the tests and follow-up diagnosis, or between the results of the tests and the outcomes of DBS, were evaluated on the basis of Kappa values. The sensitivity and specificity of predicting follow-up diagnoses in any two of the four challenges were compared by Bennett’s method [27]. The significant level was set at P < 0.05.
3. Results There were no significant differences in mean age, gender, duration of symptoms, Hoehn–Yahr stage and UPDRS-III scores between the PD group and the non-PD group at baseline (P < 0.01, Table 1).
Table 1 Characteristics of subjects who completed tests with the four doses of levodopa
Age (year, mean SD) Gender (M/F) Duration of symptoms (year, mean SD) H–Y stage ‘‘off’’ (mean SD) UPDRS-III ‘‘off’’ (mean SD)
PD group (n ¼ 112)
Non-PD group (n ¼ 63)
P *value
61.7 11.3 70/42 5.5 5.1 2.25 1.03 32.2 18.0
60.1 10.9 38/25 4.3 3.6 2.37 1.25 29.8 16.6
0.344 0.839 0.110 0.271 0.487
* P > 0.05, PD vs. non-PD parkinsonism. UPDRS, unified Parkinson’s disease rating scale.
T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
The average UPDRS-III improvement of the PD group was significantly higher than that of the non-PD group in tests with all four doses of levodopa/benserazide (P < 0.001, Table 2). Fig. 1 shows the four ROC curves from the tests. The area under the curve (AUC) of ROC curves from the tests with levodopa/benserazide was 0.834 (100/25 mg), 0.864 (150/37.5 mg), 0.903 (200/ 50 mg), and 0.913 (300/75 mg). These curves displayed statistical difference for differential diagnoses between patients with PD and those with non-PD parkinsonism (P < 0.001). When patients with PD were compared with patients with nonPD parkinsonism, the maximal Youden Indices that optimal cutoff points for UPDRS-III improvement on ROC curves could yield, in tests with the four incremental doses of levodopa/benserazide, were 0.592 (100/25 mg), 0.650 (150/37.5 mg), 0.722 (200/50 mg) and 0.715 (300/75 mg). The optimal cutoff points that achieved the best diagnostic accuracy were 12.2% (levodopa/benserazide 100/ 25 mg, sensitivity 80.2%, specificity 79%), 22.3% (150/37.5 mg, sensitivity 81.1%, specificity 83.9%), 27.9% (200/50 mg, sensitivity 88.3%, specificity 83.9%), and 33.4% (300/75 mg, sensitivity 89.2%, specificity 82.3%) (Table 3). The results of the tests showed significant consistency with the follow-up diagnoses at 24 months, with Kappa values of 0.504 (100/ 25 mg), 0.666 (150/37.5 mg), 0.694 (200/50 mg) and 0.678 (300/ 75 mg), for the four incremental doses of levodopa/benserazide (P < 0.01). At 24 months, the test with 300/75 mg of levodopa/ benserazide yielded the highest sensitivity of 89.7% and the highest NPV of 81.4%, while the test with 150/37.5 mg of levodopa/benserazide yielded the highest specificity of 85.5% and the highest PPV of 90.8%. The test with 100/25 mg of levodopa/benserazide to predict follow-up diagnosis was significantly lower in terms of sensitivity than tests with 200/50 mg or 300/75 mg of levodopa/ benserazide (P < 0.01), and significantly lower in terms of specificity than the test with 150/37.5 mg of levodopa/benserazide (P < 0.05). There was no significant difference in sensitivity or specificity between tests with any other two of the four doses (P > 0.05) (Table 4). The results of tests with 150/37.5 mg, 200/50 mg and 300/75 mg of levodopa/benserazide showed significant correlation with the outcomes of DBS (Kappa values of 0.373, 0.642 and 0.849; P < 0.01) with the exception of the test with 100/25 mg of levodopa/benserazide (Kappa ¼ 0.126, P ¼ 0.187). The PPV and NPV increased synchronously with levodopa dose. The NPVs of the tests with 100/ 25 mg and 150/37.5 mg of levodopa/benserazide were only 13.3% and 30.0%, although the PPVs were 96.0% and 98.2%. The test with 300/75 mg of levodopa/benserazide yielded a PPV of 98.4% and an NPV of 100% (Table 5). 4. Discussion Our study has established a new method of acute stepwise challenge test with incremental doses of levodopa and continuous assessment of UPDRS-III at short intervals. The strengths of our study are: First, the motor response to incremental doses of levodopa was evaluated in 175 parkinsonian patients. Second, the ROC curves of acute stepwise tests with four doses of levodopa/
ROC Curve
1.00
.75
Sensitivity
356
Source of the Curve .50
Reference Line D375MG D250MG
.25
D187.5MG D125MG 0.00 0.00
.25
.50
.75
1.00
1- Specificity Diagonal segments are produced by ties. Fig. 1. ROC curves from the acute stepwise challenge tests with four doses of levodopa/ benserazide (n ¼ 175). Red line: ROC curve of test with 100/25 mg of levodopa/benserazide (AUC ¼ 0.834, P < 0.001); Green line: ROC curve of test with 150/37.5 mg of levodopa/benserazide (AUC ¼ 0.864, P < 0.001); Blue line: ROC curve of test with 200/ 50 mg of levodopa/benserazide (AUC ¼ 0.903, P < 0.001); Purple line: ROC curve of test with 300/75 mg of levodopa/benserazide (AUC ¼ 0.913, P < 0.001). ROC, receiver operating characteristic; AUC, area under curve.
benserazide all displayed statistical difference. Third, the results of the acute stepwise tests were not only compared with follow-up diagnoses of 167 subjects, but also compared with the outcome of DBS in 63 subjects 24 months later. The critical index of a diagnostic test is the optimal cutoff point [26]. The present study showed that the optimal cutoff points for UPDRS-III improvement in challenge tests with the four incremental doses of levodopa/benserazide were 12.2% (100/25 mg), 22.3% (150/37.5 mg), 27.9% (200/50 mg) and 33.4% (300/75 mg). The discrepancies between these optimal cutoff points and those of previous studies were not only because of the different doses of levodopa used in the tests, but also due to the different methods for identifying the cutoff points. Merello et al. [15] rated the test with 250/50 mg of levodopa/carbidopa as positive or negative according to whether values reached a minimal 30% of improvement on UPDRS-III; however, Zappia et al. [13] used with the same dose of drug, but defined a result as positive when improvement on UPDRS-III was >20%. Rossi et al. [14] defined the point on the ROC curve closest to 80% sensitivity and 80% specificity as the optimal cutoff point for UPDRS-III. In the present study the ROC curves were also plotted based on the motor improvement of the two groups, with the AUC of ROCs having significant statistical difference. This suggested that the stepwise tests had discriminating ability, and it was possible to find optimal cutoff points on ROC curves for
Table 2 Improvement in UPDRS-III scores in the two groups Levodopa/benserazide
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
PD group (n ¼ 112)
Non-PD group (n ¼ 63)
Mean SD
95%CI
18.72% 8.89% 29.97% 11.54% 40.36% 13.19% 49.93% 15.32%
17.05%, 20.40% 27.80%, 32.14% 37.88%, 42.85% 47.05%, 52.81%
Mean SD
P value Median
95%CI
6.78%* 11.50%* 18.48 11.14% 22.67% 12.45%
15.65%, 21.31% 19.51%, 25.83%
* Non-normally distributed data. ** PD vs. non-PD, with Mann–Whitney test. *** PD vs. non-PD, with Student’s t-test. CI, confidence interval.
<0.001** <0.001** <0.001*** <0.001***
T. Feng et al. / Parkinsonism and Related Disorders 15 (2009) 354–358
357
Table 3 Optimal cutoff values of UPDRS-III improvement in levodopa tests (n ¼ 175) Levodopa/benserazide
Maximal Youden index*
Optimal cutoff values
Sensitivity
Specificity
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
0.592 0.650 0.722 0.715
12.2% 22.3% 27.9% 33.4%
80.2% 81.1% 88.3% 89.2%
79% 83.9% 83.9% 82.3%
* Youden index ¼ sensitivity þ specificity1.
differential diagnoses. Then, the cutoff point on the ROC curve with the maximal value of Youden index was defined as the optimal cutoff value with the best balance of sensitivity and specificity [26]. The predictive accuracy of the optimal cutoff points in the stepwise tests was assessed by follow-up over two years. The follow-up diagnoses were also made according to the UKPDSBB criteria for PD, which have the highest clinical diagnostic accuracy. These criteria for the diagnosis of PD have an estimated diagnostic specificity of 98.6% and sensitivity of 91.1% [28]. The present study shows that the results of acute stepwise challenge tests with levodopa/benserazide have significant correlation with the followup diagnosis 24 months later. As follow-up diagnosis was not a definite standard for evaluating the tests, verification by other means should also be performed. As DBS provides significant benefit to PD patients, but not patients with non-PD parkinsonism [24,25], the efficacy of DBS is a supportive item for the diagnosis of PD rather than non-PD parkinsonism. Thus, the correlation between acute challenge tests and the outcomes of DBS suggests that positive results of the tests may also predict a diagnosis of PD rather than non-PD parkinsonism. DBS can significantly improve the UPDRS-III of PD (43% at 1 year [29], 37.2% at 3 years and 35.1% at 5 years [30]), and the indication for DBS is >30% improvement in UPDRS-III score [24,25]. Thus, the outcomes of DBS were rated as effective when the improvement in UPDRS-III score was higher than 30% in the present study. The results showed that tests with 150/37.5 mg, 200/50 mg and 300/75 mg of levodopa/benserazide had statistically significant correlation with the outcomes of DBS, with the exception of the test with 100/25 mg of levodopa/benserazide. These findings provide indirect evidence that positive results in the stepwise tests may predict a diagnosis PD. The test with 100/25 mg of levodopa/benserazide was significantly lower in sensitivity to predictive follow-up diagnoses than the tests with 200/50 mg and 300/75 mg respectively, and was also significantly lower in specificity than the test with 150/37.5 mg. However there was no significant difference in sensitivity or specificity between tests with any other two of the four doses. These results indicated that any one of 150/37.5 mg, 200/50 mg or 300/75 mg of levodopa/benserazide could be used to perform an acute challenge for differential diagnoses, because of their similar sensitivity and specificity. The test with 300/75 mg of levodopa/ benserazide yielded a PPV of 98.4% and an NPV of 100% to predict the efficacy of DBS, while the NPVs of the tests with 150/37.5 mg and 200/50 mg were only 30.0% and 60.0%. These results indicated that an acute challenge test with 300/75 mg of levodopa/benserazide, rather than the other three doses, should be used as screening tool to identify potential candidates for DBS.
The diagnostic sensitivities of the optimal cutoff points in these stepwise tests ranged from 80.2% to 89.2%, and the corresponding diagnostic specificities ranged from 79% to 83.9%. In a meta-analysis review, the 95%CI of sensitivity of acute levodopa challenge for the diagnosis of established PD was between 0.64 and 0.85, while the specificity was between 0.59 and 0.80 [8]. Rossi et al. [14] showed that the levodopa test yielded a sensitivity of 77.1% and a specificity of 71.1% for differential diagnosis of parkinsonism. Merello et al. [15] reported that the overall sensitivity and specificity of acute levodopa challenge to predict clinical diagnosis of PD were 70.9% and 81.4% respectively. These results suggested that the diagnostic sensitivity and specificity achieved in the present study were superior to those achieved in previous studies. However, direct statistical comparison of predictive values between the present study and previous studies could not be made due to the heterogeneous methodologies used. Some factors that may influence the dopaminergic response should be taken into account when interpreting the results of the challenge tests with levodopa. Previously treated PD patients and never treated patients may show different levodopa responsiveness [18]; meanwhile, most patients with parkinsonism referred to undergo acute challenge tests are those without definite responsiveness after being treated with levodopa. In the present study, the enrolled subjects were all being treated for parkinsonism. Because the subjects varied in their protocol of levodopa substitution, including the duration of substitution, the dose of levodopa, and adjunctive treatment with dopamine receptor agonist, we could not compare the two groups based on matched-substitution of levodopa. The response to levodopa changes during the course of PD [20]. Nutt et al. showed that the magnitude of the response was significantly greater in more advanced stages [31]. In the present study, there was no statistical difference in the duration of motor symptoms, H–Y stage and UPDRS-III scores between the two groups, so the comparison of levodopa responsiveness between the two groups could be interpreted on the equivalent severities of movement disturbance. Parkinsonisms are clinicopathological entities, for which a definite diagnosis can only be established by autopsy [1]. In this study, the diagnosis used as standard was based on clinical criteria, and the length of follow-up was not comparable to the average survival time of patients with other forms of parkinsonism, including MSA and PSP [14,32]. There was no placebo used in the present study, because some of the typical side effects of levodopa (for example, mild nausea) could easily be identified by patients or doctors. Instrumental measurement [19], neurophysiological parameters and functional neuroimaging [9] should be employed for specific
Table 4 Ability of acute stepwise levodopa test to predict follow-up diagnosis 24 months later (n ¼ 167) Levodopa/benserazide
Sensitivity
Specificity
Youden index
Positive predictive value
Negative predictive value
Overall accuracy
Kappa value
P value of Kappa
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
77.6%* 83.2% 88.8%* 89.7%*
74.2%** 85.5%** 80.6% 77.4%
0.518 0.687 0.694 0.671
83.8% 90.8% 88.8% 87.3%
65.7% 74.6% 80.6% 81.4%
76.3% 84.1% 85.8% 85.2%
0.504 0.666 0.694 0.678
<0.01 <0.01 <0.01 <0.01
* Sensitivity: 100/25 mg vs. 200/50 mg. 100/25 mg vs. 300/75 mg, P<0.01. ** Specificity: 100/25 mg vs. 150/37.5 mg, P<0.05.
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Table 5 Ability of acute stepwise levodopa tests to predict the outcomes of DBS 24 months later (n ¼ 63) Levodopa dosage
Sensitivity
Specificity
Youden index
Positive predictive value
Negative predictive value
Overall accuracy
Kappa value
P value of Kappa
100/25 mg 150/37.5 mg 200/50 mg 300/75 mg
78.7% 88.5% 96.7% 100%
50.0% 75.0% 75.0% 75.0%
0.287 0.635 0.717 0.750
96.0% 98.2% 98.3% 98.4%
13.3% 30.0% 60.0% 100%
76.9% 87.7% 95.4% 98.4%
0.126 0.373 0.642 0.849
0.187 <0.01 <0.01 <0.01
DBS, deep-brain stimulation.
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