Article Text

Research paper
Impact of DaTscan SPECT imaging on clinical management, diagnosis, confidence of diagnosis, quality of life, health resource use and safety in patients with clinically uncertain parkinsonian syndromes: a prospective 1-year follow-up of an open-label controlled study
  1. Andreas R Kupsch1,
  2. Nin Bajaj2,
  3. Frederick Weiland3,
  4. Antonio Tartaglione4,
  5. Susanne Klutmann5,
  6. Melanie Buitendyk6,
  7. Paul Sherwin7,
  8. Ann Tate7,
  9. Igor D Grachev7
  1. 1Department of Neurology, University Medicine Berlin, Berlin, Germany
  2. 2Derbyshire Royal Infirmary, Neurology Department, Derby, UK
  3. 3Sutter Health, Roseville, California, USA
  4. 4Department of Neurology, S. Andrea Hospital and Ass. Sistema Nervoso, La Spezia, Italy
  5. 5Department of Nuclear Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  6. 6i3 Statprobe, Burlington, Ontario, Canada
  7. 7Clinical Development, GE Healthcare, Princeton, New Jersey, USA
  1. Correspondence to Dr Igor D Grachev, Clinical Development, GE Healthcare, Princeton, NJ 08540, USA; igor.grachev{at}ge.com

Abstract

Background This study assessed the impact of DaTscan on clinical management, diagnosis, confidence of diagnosis (CoD), quality of life (QoL), health resource use (HRU) and safety during a 1-year follow-up in patients with clinically uncertain parkinsonian syndromes (CUPS).

Methods A total of 19 university hospital centres in Europe and the USA participated in this open-label, single-dose, prospective, clinical trial in patients with CUPS who were randomised to a DaTscan imaging group or to a no-imaging (control) group. The proportion of patients with changes in clinical management, diagnosis, CoD, QoL and HRU from baseline through 1 year post-DaTscan was compared between groups.

Results There were 273 patients randomised (135 DaTscan, 138 control). Significantly more patients in the DaTscan imaging group had at least one change in their actual clinical management after 12 weeks (p=0.002) and after 1 year (p<0.001) compared with patients in the control group. In addition, significantly more DaTscan patients had changes in diagnosis and an increased CoD at 4 weeks, 12 weeks and 1 year (all p<0.001) compared with control patients. No significant differences in total score for QoL or HRU were observed between groups during the 1-year follow-up period. DaTscan was safe and well tolerated. One patient in the imaging group had an adverse event (headache) with suspected relationship to DaTscan post-administration.

Conclusions DaTscan had a significant impact on clinical management, diagnosis and CoD in patients with CUPS. DaTscan is safe and well tolerated, and is a useful adjunct to differentiate a diagnosis of CUPS.

Trial registration number http://ClinicalTrials.gov Identifier: NCT00382967.

  • DaTscan
  • SPECT
  • parkinsonian syndromes
  • clinical management
  • diagnosis
  • neuropsychology
  • neurophysiology
  • clinical
  • dementia
  • Alzheimer's disease
  • consciousness
  • nuclear medicine
  • Parkinson's disease
  • pet

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Introduction

Idiopathic Parkinson's disease (PD) is the second most common neurodegenerative disorder and the most prevalent type of parkinsonian syndrome (PS) with overall incidence of approximately 17 per 100 000 per year.1 2 Clinical diagnosis is based on presence of fatiguable bradykinesia with one other symptom: tremor, rigidity or postural instability.3 4 In PD or PS with dopaminergic deficit, characteristic motor signs and symptoms do not emerge until the degenerative process is well established (>60% loss of striatal dopamine).5–8 Diagnosis of these disorders can be challenging, especially in the early stages when symptoms have not fully emerged or patients present with atypical signs. In addition, the literature suggests a trend towards over-diagnosis of PD,9–12 resulting in inappropriate treatment of patients with anti-Parkinson's medication.13 Approximately one in five patients with suspected PS are classified as clinically uncertain PS (CUPS).14

DaTscan ([123I]Ioflupane Injection; DaTscan is the approved name in the USA and DaTSCAN is the approved name in the European Union) is a radiopharmaceutical approved in Europe and the USA, used for single-photon emission CT brain imaging. DaTscan binds to the dopamine transporter membrane (as opposed to vesicular) located on presynaptic terminals of dopaminergic neurons,15 16 and thereby, identifies loss of functional dopaminergic neuron terminals.

DaTscan has been shown to help clinicians optimise diagnostic accuracy and plan clinical management in most PS cases.14 Because essential tremor involves no loss of dopaminergic neurons, the use of DaTscan assists clinicians in distinguishing between essential tremor and dopaminergic-deficit PS.17–20 When DaTscan images are abnormal, patients with diagnostic uncertainty between PS and essential tremor have a greater likelihood of PS and when DaTscan images are normal, a very low likelihood of PS.9 17

Some studies even suggest that in cases of early, suspected PS, DaTscan imaging results may be more accurate than a clinical diagnosis alone.21 In patients with CUPS, a high degree of agreement (90%) between the initial DaTscan image and the clinical diagnosis at 2-year follow-up has been reported.22 A meta-analysis by Vlaar and colleagues23 examined 32 studies and concluded that SPECT with presynaptic tracers is accurate in differentiating patients with early phase PD from normals and patients with PD from those with essential tremor or vascular parkinsonism.

With the prevalence of PD predicted to rise due to an ageing population, the need for an accurate diagnosis, allowing for the timely initiation of appropriate treatment and counselling, has been highlighted as a priority by organisations including the National Service Framework for Long-Term Conditions and the National Institute for Health and Clinical Excellence.24 The objective of our study was to assess the impact of DaTscan imaging on clinical management plans, clinical diagnosis, confidence of diagnosis (CoD), quality of life (QoL), health resource use (HRU) and safety during a 1-year follow-up period in patients with CUPS at centres involving general neurologists both with and without movement disorder specialisation, reflecting real-life clinical practice. The interim results of this study after the 12-week follow-up were presented at the 2011 American Academy of Neurology annual meeting.25

Methods

All study protocols, amendments and informed consent documents were approved by the appropriate ethics committees or institutional review boards prior to starting the study. Prior to the initiation of any study procedures, informed consent was obtained from participating patients. This study was conducted in full accordance with the Declaration of Helsinki (World Medical Association), the International Conference on Harmonisation consolidated guideline E6 Good Clinical Practice, and applicable national and local laws and regulations.

Study design and eligibility

This was a randomised, open-label, single-dose, prospective, multicentre, comparative clinical trial to assess the impact of DaTscan SPECT imaging on clinical management, diagnosis, CoD, QoL, HRU and safety in patients with CUPS, covering baseline (Visit 1) and follow-up assessments at 4 weeks, 12 weeks and 1 year (Visits 2, 3 and 4, respectively).

The main inclusion criteria were: (1) specified diagnosis of CUPS, or monosymptomatic, atypical, or incomplete presentation of parkinsonian signs and symptoms, and (2) onset of clinical manifestations of Parkinsonian signs and symptoms within 5 years prior to enrolment. Main exclusion criteria were: (1) a differential diagnosis between PD and either progressive supranuclear palsy or multiple system atrophy, (2) a diagnosis of established or certain movement disorder, (3) presence of known causes of tremors (eg, hyperthyroidism), (4) significant cognitive impairment (mini-mental state examination score <24), or (5) concomitant medication suspected to interact with striatal uptake through direct competition with dopamine transporter binding, not discontinued for at least five half-lives (eg, amphetamine, benztropine, bupropion, cocaine, mazindol, methylphenidate, phentermine and sertraline). Patients were considered to have a diagnosis of CUPS when the clinical data posed significant uncertainty to the neurologist to establish a clinical diagnosis of parkinsonism. Criteria of uncertainty were assessed by referring neurologists, and included at least one of the following: only one of the three cardinal signs of parkinsonism, with or without asymmetry; two signs without bradykinesia; atypical signs; signs of mild intensity; poor response to L-dopa and lack of disease progression.14

Study treatments and assessments

Visit 1 (baseline/randomisation) included assessments of demographics, medical history, neurological evaluation, modified Hoehn and Yahr staging,26 establishment of a clinical diagnosis (including reasons for uncertain diagnosis) and assessment of planned clinical management. Randomisation cards were prepared at a central location and shipped to centres. Based on the treatment assignment on the card, patients were randomised to either the DaTscan imaging group or the no-imaging (control) group. In addition, patients completed the disease-specific QoL measure, the 39-Item Parkinson's Disease Questionnaire (PDQ-39)27 and the generic European QoL-5 Dimensions (EQ-5D, including mobility, self-care, usual activities, pain/discomfort and anxiety/depression).28

Prior to Visit 2, patients in the DaTscan group underwent intravenous administration of a single dose (111–185 MBq or 3–5 mCi, maximum volume 5 ml) of DaTscan via the antecubital vein, while in a supine or recumbent position, with SPECT imaging of the head 3 to 6 h later. Thyroid blocking was performed according to local hospital routines. Images were assessed visually by the same nuclear medicine physician (expert in neuroimaging) at each centre. Images were classified as normal (figure 1A), abnormal type 1 (figure 1B), abnormal type 2 (figure 1C) or abnormal type 3 (figure 1D). The normal or abnormal determination was made by assessing the extent (as indicated by shape) and intensity of the striatal signal. Image interpretation did not involve integration of the striatal image with clinical signs and/or symptoms to preserve blind. This study was designed to include one blinded reader at each centre to be in line with current clinical practice. There was an option to have a second reader evaluation if the primary reader was unclear on image interpretation.

Figure 1

Normal and abnormal DaTscan SPECT Images. (A) Normal DaTscan SPECT image: characterised by uptake of the tracer in both right and left putamen and caudate nuclei. The image was largely symmetrical with approximately equal levels of uptake on both left and right sides. Activity was contained close to the centre image, forming two crescent-shaped areas of uptake. Abnormal DaTscan images fall into at least one of the following three categories (all are considered abnormal). (B) Abnormal DaTscan SPECT image type 1: included asymmetrical uptake with almost normal or reduced putamen activity in one hemisphere and a more marked change on the other side, likely on the side opposite the patient's first clinically affected side, and characterised by a significantly lower or no uptake in the putamen. The uptake was limited to a roughly circular area. (C) Abnormal DaTscan SPECT image type 2: included significantly reduced putamen uptake on both sides. Activity was confined to the caudate nuclei and formed two roughly circular areas. (D) Abnormal DaTscan SPECT image type 3: had virtually no uptake from both the putamen and caudate nuclei on both sides of the brain, resulting in a significant reduction in contrast and the visualisation of background activity throughout the rest of the image.

All subjects were imaged on a dual or triple head SPECT camera fitted with low energy high resolution collimators, either parallel hole or fanbeam collimators (including ultra-high resolution fanbeam collimators). The same camera/collimator system was used for all subjects. All SPECT imaging was performed with the camera heads positioned as close as possible to the subject's head to achieve a radius of rotation that was as small as possible. When the SPECT acquisition was completed, the projection images were checked for motion artefacts or dropped frames before the subject was dismissed. Unprocessed projection data were reviewed in cinematic display or in sinogram form. If artefacts were noted, the imaging was repeated starting no later than 6 h post-injection. Each centre had a nuclear medicine computer system capable of reconstructing the acquired SPECT projection images using filtered backprojection and applying a linear (Chang) attenuation correction (see online supplementary tables).

For the DaTscan group, safety parameters, including adverse events (AEs) and serious adverse events, were collected from the start of the DaTscan imaging visit until completion of the SPECT imaging. Treatment-emergent safety parameters were not collected for the control group.

Patients were evaluated for changes in clinical management plan, diagnosis and CoD at Visit 2, 4 weeks (±1 week) after Visit 1; Visit 3, 12 weeks (±2 weeks) after Visit 1; and Visit 4, 1 year (±4 weeks) after Visit 1. The data collection on these changes was not cumulative. Diagnoses for PS included PD, vascular parkinsonism, drug-induced parkinsonism, other PS, precise PS diagnosis not available; diagnoses for non-PS included essential tremor, other non-PS and precise non-PS diagnosis not available. Change in diagnosis included a change in any of these diagnoses. Inconclusive diagnoses were also included in this analysis.

QoL measures and HRU were collected at 12 weeks and 1 year. Patients were also given a diary to record healthcare visits, diagnostic procedures and medication changes.

Statistical analysis

Patients who received DaTscan injections, together with control patients who had Visit 1 evaluations, formed the safety population. The efficacy population consisted of patients who had a baseline clinical management plan and attended Visits 1 and 3; the per-protocol population consisted of subjects who attended all four visits (see figure 2). The sample size was based on assuming that the probability of change in clinical management would be 60% for patients in the DaTscan group and 40% for patients in the control group, such that 108 patients in each study group would yield 80% power to detect a 20% difference between the groups with α=2.5. With 10–15% expected dropout, approximately 250 patients were to be enrolled.

Figure 2

Study diagram showing patient disposition between DaTscan and control groups for safety, efficacy and per-protocol populations. Safety population = patients who received DaTscan injection + control patients who had Visit 1 evaluations. Efficacy population = patients who had a baseline clinical management plan and attended Visits 1 and 3. Per-protocol population = patients who attended all four visits.

The primary endpoint was the proportion of patients in the efficacy population who had one or more changes in clinical management from baseline to 12 weeks. The proportion of patients with a change in their clinical management was compared between groups using a one-sided Fisher's exact test with α=0.025; proportions were estimated with 95% CIs. As a secondary endpoint, this analysis was performed for patients in the efficacy population who had a change in clinical management from baseline to 1 year. All other secondary endpoints were analysed for the per-protocol population. The proportion of patients with changes in suspected clinical diagnosis was compared between groups using a two-sided Fisher's exact test, and the mean per cent change in CoD was compared using a one-sided t-test. The scores on the eight dimensions from the PDQ-39 were assessed for association with study group by analysis of covariance (ANCOVA) using QoL, diagnosis and other relevant variables at baseline as covariates. The health status visual analogue scale scores from the EQ-5D were also assessed using ANCOVA. Scores from the five sections of the EQ-5D were summarised, and the change in total score was analysed using the Wilcoxon–Mann–Whitney test. Data on HRU were collected from baseline through 1 year and compared using a one-sided Fisher's exact test. The incidence of treatment-emergent AEs was reported for the DaTscan group of the safety population. Analysis between investigator expertises was done using a logistic regression model by treatment group.

Results

Patient disposition and baseline characteristics

Figure 2 shows patient disposition. A total of 273 patients were enrolled and randomised across 19 centres in Europe and the USA. Of the 135 randomly assigned to the imaging group, 122 received DaTscan injections and were imaged. The mean volume of DaTscan administered was 2.3 ml (SD: 0.66) with a mean radioactivity of 171.1 MBq (SD: 12.46; 121 to 203 MBq dose range) over a mean infusion duration of 2.0 min (SD: 0.88). Patient demographics and movement disorder history are presented in table 1.

Table 1

Patient demographics and movement disorder history (safety population)

At baseline, 165 (64%) patients had a diagnosis of PS, 63 (24%) had a diagnosis of non-PS and 31 (21%) had an inconclusive diagnosis. Neurological examination results at baseline are presented in table 2. Overall, the most frequent reasons for CUPS diagnosis were atypical signs [146 (56%) patients], one of the three cardinal signs of PS [92 (36%)], poor response to L-dopa [51 (20%)] and two signs without bradykinesia [45 (17%)]. The reasons for CUPS diagnosis were comparable between groups at baseline. The proportion of patients who took nervous system medications during the study was comparable between groups (table 3).

Table 2

Neurological examination at baseline (safety population)

Table 3

Nervous system concomitant medications (safety population)

Changes in clinical management plan, diagnosis and confidence of diagnosis

In the efficacy population (N=244), significantly more patients in the DaTscan group (50%) had at least one change in clinical management by 12 weeks compared with patients in the control group (31%) (p=0.002; table 4). Similar results were observed at the 1-year follow-up visit: 41% of patients in the DaTscan group had at least one change in clinical management compared with 22% of patients in the control group (p<0.001). The most frequent change in clinical management across both groups at 12 weeks and 1 year was initiation of medication not planned at baseline (see online supplementary tables). In the per-protocol population (N=215), 50% of patients in the DaTscan group had changes in clinical management at 4 weeks compared with 21% of patients in the control group.

Table 4

Changes in clinical management and diagnosis from baseline (Visit 1) to 12 weeks (Visit 3) and 1 year (Visit 4)

In the per-protocol population, significantly more patients in the DaTscan group had a change from baseline in diagnosis compared with the control group at all follow-up visits (p<0.001, table 4). Namely, changes in diagnosis between baseline and 4 weeks (after DaTscan results were available) occurred in 45% of the DaTscan group, compared with 9% of the control group. The changes in diagnosis between baseline and 12 weeks or between baseline and 1 year occurred in 46% and 54%, respectively, of patients in the DaTscan group, compared with 12% and 23% of patients in the control group. These changes were in direction of better agreement between clinical diagnoses (eg, PS vs non-PS) and imaging results (eg, abnormal vs normal) in the DaTscan imaging group (see online supplementary tables). The CoD at baseline, prior to DaTscan imaging, was similar between groups for patients with any suspected diagnosis. However, after DaTscan imaging, the CoD for patients with a suspected diagnosis of PS or non-PS was higher at 4 weeks, 12 weeks and 1 year in the DaTscan group compared with the control group (table 5). A significantly greater mean change from baseline in CoD was observed in the DaTscan group at all follow-up visits compared with the control group (p<0.001 for all visits and diagnoses, table 5). The comparison between mean percent change in diagnosis and mean percent change in CoD from baseline to 12 weeks and 1 year is shown in figure 3. These data show that the changes in diagnosis were in the same direction as changes in CoD in the DaTscan group, compared with the control group.

Table 5

Mean percent change in confidence of diagnosis from baseline (per-protocol population)

Figure 3

Mean percent change in diagnosis as compared with mean per cent change in confidence of diagnosis (CoD) in the per-protocol population: (A) From baseline to Visit 3 (12 weeks), (B) From baseline to Visit 4 (1 year).

Because this study was conducted by both general neurologists (n=7) and movement disorder specialists (n=12), comparisons in clinical management and change in diagnosis were made to determine if there were differences in results between the two types of investigators. No statistically significant difference between the two investigator types in change in clinical management was found using a logistic regression model. However, within movement disorder specialists, changes in clinical management between DaTscan and the control group were significant at 12 weeks (51% vs 28%, p<0.001) and at 1 year (40% vs 19%, p<0.001), no significant changes were seen within general neurologists. In the DaTscan group, change in diagnosis at 1 year was found to be significantly higher among general neurologists (75%) compared with movement disorder specialists (47%; p=0.022) (see online supplementary tables).

Quality of life and health resource use

The visual analogue scale health status scores and patient responses on the EQ-5D QoL questionnaire were similar between the DaTscan and the control group. At 12 weeks, a small non-significant improvement was observed in PDQ-39 total scores compared with baseline in both groups. At 1 year, patients in the DaTscan group had further non-significant improvements in PDQ-39 total scores, whereas scores in the control group were similar to baseline. At 12 weeks, 31 (33%) patients in the DaTscan group and 40 (38%) patients in the control group reported using at least one health resource since baseline. Fewer patients in the DaTscan group (16 patients (17%)) compared with the control group (27 patients (26%)) reported a visit to their family doctor between baseline and 12 weeks, although this difference was not statistically significant (p=0.094). Between 12 weeks and 1 year, HRU was similar across groups.

In an effort to further explain the observed non-significant effects on QoL, we compared CUPS patients (in the DaTscan imaging group) with normal versus abnormal scans and found no difference in QoL (non-parametric one-sided Wilcoxon two-sample test). Hoehn & Yahr stage was only assessed at baseline and no significant difference was found between patients with normal versus abnormal scans (non-parametric two-sided Wilcoxon two-sample test). However, analyses for HRU found differences in hospitalisations (there were seven hospitalisations within 52 CUPS patients with an abnormal scan and 0 within 50 CUPS patients with a normal scan, p=0.007).

Safety

In the DaTscan group, two patients (2%) experienced an AE prior to DaTscan administration: influenza-like illness and a single fall. A third patient was withdrawn prior to receiving DaTscan due to dizziness experienced during Visit 1.

Following DaTscan administration, one (1%) patient experienced a single AE of sleep disorder, not considered related to DaTscan; and one (1%) patient experienced a single AE of headache with a suspected causal relationship to DaTscan because the onset occurred between DaTscan dosing and SPECT imaging. The headache was mild, resolved within 2.5 h, and required no treatment. No serious AEs or deaths occurred during the study.

Discussion

The primary aim of our study was to assess the impact of DaTscan imaging on the clinical management, diagnosis, CoD, QoL, HRU and safety in patients with CUPS over 1 year. Our study is unique in that the design included random assignment to either an imaging group or a no-imaging group, and prospectively documented and assessed changes in clinical management over 1 year. A potential limitation of our study is that the study design was not blinded and investigators were aware of the protocol's objectives and hypotheses; however, it is difficult to conceive how this awareness may have influenced the investigators' clinical management decisions. Another limitation is the lack of neuropathological confirmation of the diagnosis; however, the validity of our approach is supported by studies that correlate DaTscan image assessment with the neuropathological diagnosis determined at autopsy as the standard-of-truth. Results showing a good correlation between DaTscan and neuropathology have been published.29

DaTscan has high specificity and sensitivity in distinguishing PS from non-PS. However, an abnormal DaTscan does not give a diagnosis per se, as a number of PS patients will give a similarly abnormal scan. However, an abnormal DaTscan does allow exclusion of non-PS, which narrows the differential diagnosis in CUPS and may increase physician confidence in formulating a final clinical diagnosis and in turn an appropriate clinical treatment plan.

Following an interim analysis of our data, we previously reported that significantly more patients in the DaTscan group had a change in their clinical management at approximately 12 weeks post-treatment compared with patients in the control group.25 Similar results were obtained at 1-year follow-up, with significantly more patients in the DaTscan group (41%) having a change in clinical management compared with the control group (22%).

DaTscan results influenced clinical management in a number of ways including more aggressive dopaminergic therapy in patients with abnormal scans who had a suboptimal drug response prior to study inclusion, initiation of dopaminergic therapy in abnormal scan patients where treatment had not been started prior to study inclusion, discontinuation of dopaminergic drug therapy in some patients where DaTscan was normal, initiation of tremor control drugs (eg, primidone, propranolol, clonazepam or anti-cholinergics) in DaTscan normal tremulous patients, and also performance of unplanned diagnostic tests.

Our study also demonstrated that DaTscan imaging resulted in significantly more changes in clinical diagnosis at 4 weeks, 12 weeks and 1 year. From 45% to 54% of patients who underwent DaTscan had their diagnosis changed over 1 year compared with 9% to 23% in the control group: changes were towards better agreement between clinical diagnoses and imaging results (patients with abnormal scans were more likely to have a diagnosis of PS, and subjects with normal scans were more likely to have a diagnosis of non-PS). This finding supports the current literature, which suggests a tendency towards misdiagnosis of PD in routine clinical practice9 12 and highlights the need to improve clinical diagnostic accuracy in order to ensure that timely, appropriate, therapeutic interventions are implemented for the right patients. We also observed that DaTscan imaging resulted in a significant increase in physicians' CoD at all follow-up visits compared with the control group, indicating that DaTscan is a valuable aid to clinically based diagnosis of PS.

Our findings agree with other reports that demonstrate DaTscan assists in the clinical diagnosis and influences the management of patients with uncertain parkinsonism. A multicentre, non-randomised trial of 118 patients with CUPS showed that DaTscan resulted in a change in neurologists' diagnoses in 52% of patients, increased CoD, and led to changes in clinical management in 72% of patients14; similar to our study, changes in management involved primarily initiation of new therapy. A previous retrospective evaluation of 90 patients with a tentative diagnosis of PD or parkinsonism-plus syndrome showed that DaTscan resulted in a change in treatment, management, or diagnosis in 27% of patients,30 which was lower than our prospective study. Another retrospective study of 312 patients with PS reported that 25% of patients had their initial clinical diagnoses reclassified after DaTscan12 and a study on a national registry of 1701 patients with CUPS showed that initial diagnosis was changed in 51% of patients and management was altered in 49% of patients after DaTscan31; both frequencies are similar to those observed in our study.

Additionally, because the participants were predominantly imaging centres involving movement disorder specialists with a high level of expertise, we compared the endpoints of change in clinical management and change in diagnosis between movement disorder specialists and general neurologists. No significant difference was found for change in clinical management between these two types of investigators; however, change in diagnosis at 1 year in the DaTscan group was significantly greater among general neurologists (75%) compared with movement disorder specialists (47%), which can be explained by a much higher impact of a supplemental diagnostic imaging test on clinical decisions among physicians who are less trained in movement disorders. Although movement disorder specialists changed their diagnosis less frequently as compared with general neurologists, the quality of their differential diagnosis was much higher and significant as compared with the control group. Recently, it has been reported that agreement in diagnosis with DaTscan improved from 66% to 90% when skilled neurologists made the diagnosis.32

The second aim of our study was to assess the impact of DaTscan on patient QoL and HRU at 12 weeks and 1 year after imaging. Parkinson's disease is known to interfere with various aspects of QoL.33–36 Studies on how a delay in diagnosis may impact the QoL in patients with CUPS are lacking; however, a delay in making an accurate diagnosis or the need to revise an incorrect diagnosis can lead to significant psychological stress for both patients and their caregivers.24 37 In our study, we did not observe a significant difference in EQ-5D or PDQ-39 QoL total scores between groups at 12 weeks or 1 year following DaTscan. One explanation is that there may be a time lag after change in clinical management plan to when significant improvements in multidimensional QoL measures appear. The 1-year follow-up was considered a minimum period for exploring clinically meaningful changes in QoL after DaTscan; however, this time period was not sufficient to observe changes in multiple dimensions. The results of the PDQ-39 lend support to this hypothesis—patients in the DaTscan group showed improvements in total scores at 1 year whereas scores in the control group were similar to baseline. It is also possible that significant differences in QoL were not observed because the instruments used are not specific to patients with CUPS. Published data and validated questionnaires for uncertain parkinsonism are lacking; therefore, we opted to use a generic questionnaire (EQ-5D) and the PDQ-39, which has been validated for PD.

Because data on HRU in patients with CUPS are limited, our study also investigated the impact of DaTscan on use of healthcare resources. A previous single-centre, university-based study found that although SPECT imaging increased initial costs, it improved the use of early adequate treatment in cases where clinical diagnosis was uncertain.38 Another cost-effectiveness study using a pharmaco-economic model based on a registry of 1701 patients with CUPS showed that the initial cost of DaTscan was small compared with the total indirect treatment costs over a 5-year period; the additional costs of imaging was offset by a strong significant gain in adequately treated years on a population basis.31 At 12 weeks and 1 year, HRU in this study was not statistically different between groups. A 1-year follow-up was considered the minimum time period for exploring any clinically meaningful changes in HRU; however, this may not have been long enough to detect statistically significant changes. Although the difference did not reach statistical significance, it was notable that the number of patient visits to the family doctor in the first 12 weeks after imaging was lower in the DaTscan group compared with the control group.

In an effort to further explain the observed non-significant effects on QoL, we compared CUPS patients (in the DaTscan group) with normal versus abnormal scans and found no significant difference in QoL. Furthermore, there was no significant difference in baseline Hoehn & Yahr stage between patients with normal versus abnormal scans. These findings further support that the majority of patients were in early stage of disease, and that 1 year is likely too short a timeframe to start observing benefits in QoL. However, analyses for HRU found there were significantly more subjects with hospitalisations that had an abnormal image scan, which further support a clinical utility of DaTscan in terms of clinical management of patients with neurodegenerative PS.

The safety of DaTscan in our study is similar to reports in the literature. One treatment-related AE of mild headache was reported after DaTscan injection. Other studies using DaTscan reported none or few AEs.11 14 16 22 These results support DaTscan as a safe and well-tolerated radiopharmaceutical agent in patients with CUPS.

Conclusions

This study was, to our knowledge, the first controlled and largest worldwide prospective trial including the USA experience, using selected endpoints in patients with CUPS. By providing evidence for the presence or absence of dopaminergic degeneration and hence the underlying pathophysiology, DaTscan SPECT imaging had a significant impact on the clinical management, diagnosis and CoD of patients presenting with CUPS. Although significant changes in QoL or HRU were not observed here, use of longer follow-up periods is warranted in future investigations. As seen in other studies, DaTscan was safe and well tolerated. Our study supports that DaTscan is a valuable tool in assisting physicians, particularly general neurologists and movement disorder specialists, in making an accurate clinical diagnosis, and thereby may play an important role in ensuring timely appropriate initiation of therapeutic management plans in patients with CUPS.

Acknowledgments

The following clinical investigators participated in the trial: Andreas Kupsch, Ana Garcia, Doreen Gruber, Henriette Krug, Elmar Lobsien, Thomas Trottenberg at Charite Campus Virchow, Department of Neurology, and Michail Plotkin at Department of Nuclear Medicine, Berlin, Germany; Carsten Buhman, Ute Hidding at Ambulanzzentrum des UKE GmbH Bereich Neurologie University Hospital Hamburg-Eppendorf, Hamburg, Germany; Helen Roberts, Vanessa Pressly at Southampton General Hospital, Department of Geriatric Medicine, Southampton, UK; Nin Bajaj, Vamsi Gontu, at Derbyshire Royal Infirmary Neurology Department, Derby, UK; Urs Pato at Inselspital Bern Neurologische Universitätsklinik and Poliklinik, Bern, Switzerland; Tove Hauge, Berd Mueller at Nordmøre og Romsdal HF Molde Hospital, Neurology Department, Molde, Norway; Pierre Charpentier, Bachir Makki at Centre Hospitalier de Béthune, Neurology Department, Bethune, France; Antonio Tartaglione, Elena Carabelli, Lucia Baruzzo, Federica Vivarelli, Department of Neurology, and Antonella Montepagani, Department of Nuclear Medicine, Ospedale S. Andrea, La Spezia, Italy; Juan Carlos Martinez Castrillo, Maria Eugenia Rioja, Jaime Masjuan at Hospital Ramón y Cajal de Madrid, Madrid, Spain; Jose Balseiro Gomez at Hospital Universitario de Getafe, Neurology Department, Madrid, Spain; Maria Dolores Escriche Jaime, Andreas Serena Puig at Hospital Meixoeiro de Vigo, Vigo, Spain; Jan Aasly, Harald Johnsen at St. Olavs Hospital HF, Neurology Department, Trondheim, Norway; Jesper Clausen at KAS Glostrup Hospital, Neurology Department, Glostrup, Denmark; Donald Grosset, Katherine Grosset at Glasgow Southern General Hospital, Glasgow, UK; Robert Hauser, Deborah Burke, Theresa McClain at University of South Florida, Tampa, Fl, USA; Mark Stacy, Burton Scott, Ralph Coleman, Julia Johnson at Duke University Movement Disorders Center, Durham, NC, USA; Danna Jennings, Kenneth Marek, David Russell at Institute for Neurodegenerative Disorders, New Haven, CT, USA; and Frederick Weiland, Nadine Yassa, Penny Vande Streek, Nicklesh Thakur at Sutter Health, Roseville, CA, USA. The authors also acknowledge the contributions of Bianca Müller for help in the clinical organisation of the trial; and Ally Gasco, i3 Statprobe, and Anne B Giordani, Winfield Consulting who collaborated in manuscript preparation. This study was sponsored by GE Healthcare, Princeton, NJ, USA. GE Healthcare, Princeton, NJ, USA entered into contract with i3 Statprobe for data management, statistical programming and analysis, and medical writing support. Editorial and financial support for this publication was provided by GE Healthcare to i3 Statprobe.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Funding This study was sponsored by GE Healthcare, Princeton, NJ, USA.

  • Competing interests PS, AT and IDG are employees of GE Healthcare. MB is employee of i3 Statprobe. ARK, NB, FW, AT and SK declare no competing interests.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by 19 different institutional ethics committees and institutional review boards (one per centre) in Europe and the USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement MB from i3 Statprobe had full access to the raw data set and takes responsibility for the integrity of the data and the accuracy of the data analysis. All results of the study were shared among all co-authors.

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