Referral practice, reporting standards, and the impact of dopamine transporter scans done in a tertiary hospital
Aims: We studied the referral practice, reporting standards, and the impact of 123 ioflupane single photon emission computed tomogram dopamine transporters (DAT-SPECT) scans conducted for the diagnosis and clinical management of patients.
Keywords: Dopamine, idiopathic, nuclear, parkinsonism, scan
Dopaminergic transport abnormality plays an integral part in the pathogenesis of degenerative Parkinsonism More Details. 123I-ioflupane is a molecular imaging agent used in single photon emission computed tomogram (SPECT) to demonstrate the location and concentration of dopamine transporters (DAT) in the synapses. DAT is the presynaptic transmembrane protein of the dopaminergic synapses. It transports dopamine from the synaptic cleft back into the presynaptic neuron. This agent has demonstrated efficacy in detecting presynaptic nigra-striatal dopaminergic degeneration early and helps in differentiating presynaptic from postsynaptic parkinsonism. However, it does not distinguish various subtypes of presynaptic or degenerative parkinsonism.,,,, The European Medicine Agency approved DAT scan (123I-Ioflupane SPECT) in 2000 and the Federal Drug Administration (FDA) approved DAT scan in 2011 for commercial use. The European Association of Nuclear Medicine (EANM) published its updated guidelines on DAT imaging in 2010. The Society of Nuclear Medicine and Molecular imaging (formerly the Society of Nuclear Medicine-SNM) published its international guidelines in 2012.,
We studied all DAT imaging performed over a 1-year duration (2013) at the Mater Misericordiae University Hospital (MMUH). We analyzed the DAT scan referral practice (indications for the scan, completeness of the requisition form, patient information, correlation with computed tomogram (CT) or magnetic resonance imaging (MRI) of the brain imaging, and reporting quality) as well as its impact on the management of patients. This is the second detailed cross-sectional study on DAT scans performed in Ireland, following a review of the DAT imaging at the Cork University Hospital.
We collected and analyzed all requisitions/orders, official results of DAT imaging done in 2013 in our Nuclear Medicine Department against the EANM 2010 and SNM 2011 practice guidelines. We collected the details of the actual clinical indication for the DAT scan, the methodology including patient preparation, patient information leaflet, tracer molecule used, and the method of analysis. The pre- and post-DAT scan diagnosis and clinical management details were also analyzed from the clinical letters to assess the impact of the scan.
The Microsoft XL 2010 and Graphpad software were used for the statistical analysis of data. A P value less than 0.05 was considered to be statistically significant. DAT uptake grading proposed by the Food and Drug Administration (FDA) and Movement Disorders Study Group were used for the grading of the scan abnormalities.,
A normal DAT scan appears like a full-stop (caudate nucleus) with a comma (putaminal tail). Grade 1 abnormality appears like a “full-stop with a disappearing coma” (asymmetrical loss of putaminal tail), grade 2 shows “two full-stops” (bilateral loss of putaminal tails), and grade 3 shows “disappearing full stops” (partial to complete loss of caudate and putaminal signals) [Figure 1]a, [Figure 1]b, [Figure 1]c.
The images were obtained 3 h after 185 megabecquerel (MBq) contrast 123 Ioflupane injection. The radioactive tracer Ioflupane 123 uptake was quantified and compared to the background activity using automated General Electric (GE) software Healthcare, Chicago, US. The overall assessment of the striatal DAT uptake was a combination of visual assessment and semiquantitative assessment. The caudate nuclei on both sides and the both putaminal uptake were measured using the GE software. An uptake ratio of less than 2 was considered as an abnormal value.
Forty eight DAT scans were performed in 2013 in MMUH. Of the 48 patients, 20 were women and 28 were men. The mean age of our patients was 68 ± 13.144 years (range: 24–91 years). Only 9 patients were below the age of 60 years. The below-60 cohort showed abnormality in 5 out of 9 DAT imaging. However, the differences seen in the abnormal outcome of DAT imaging between the below and above-60 group were not statistically significant (P > 0.05). The interval between the request for the scan and the official report was 94.39 ± 64.88 days (median: 96 days and range: 2–221 days).
The requisition form lacked any details regarding the relevant medical history or history of renal or liver impairment, which could interfere with the metabolism and excretion of the isotope, in more than 85% cases. Only 10 (22%) scans mentioned prior brain imaging, which can be helpful in the appropriate interpretation of the DAT imaging in certain circumstances [Table 1].
The indications for the 123I-Ioflupane SPECT (DAT) scan included the following: To diagnose idiopathic Parkinson's disease (IPD) or degenerative parkinsonism in 25 patients, to distinguish drug-induced parkinsonism from IPD in 8 patients, to distinguish between essential tremor (ET) and parkinsonism in 5 and 2 patients each, to distinguish Lewy body disease (LBD) from Alzheimer's disease, and dopa-responsive dystonia from parkinsonism, and to diagnose early corticobasal degeneration. Four scans were done for indications outside the reference guidelines (looking for asymmetry in the scan in possible multiple system atrophy (MSA) in 2 patients, in distinguising IPD from LBD/vascular parkinsonism, and in assessing disease progression in IPD).
Fifty four per cent of the scans (26 out of 48) were abnormal (positive), 16 were normal, and 6 scans were equivocal. Among the abnormal scans, 10 were asymmetrical bilaterally and 2 were symmetrically abnormal. Six scans showed an unilateral abnormality. However, 8 DAT reports did not comment upon symmetry, even though the scans were reported as abnormal.
The request form did not comment upon the use of certain drugs such as cocaine, amphetamine, modafinil, and bupropion that can interfere with the DAT scan interpretation. Only 12% of the requests contained information about the past neurological history such as stroke or brain tumor that might affect the DAT imaging interpretation. Only 22% of the requests cited previous brain morphological imaging such as MRI/CT scans. The patient information leaflet omitted certain information such as any potential detrimental effect of 123 Ioflupane in patients with severe renal disease and the need for sedation in anxious patients [Table 2].
The procedure section of the report complied with most of the suggested guidelines; however, it failed to mention the tracer molecule used in 5% cases. Only 1 report cited the amount of radiation exposure. The typed report correlated with the clinical question being asked in 100% cases and clearly cited the outcome of the DAT scan in all patients [Table 3].
Approximately 82% of the abnormal scans showed grade 2 defect. In the equivocal scans, the tracer uptake in the posterior striatum was in the low normal range. In these scans, 3 had a low normal tracer uptake in the left striatum, 2 had a low uptake in the right striatum, and 1 had a low uptake on both the sides [Table 4].
In twenty three percent (11 out of 48) of the scans, the diagnosis and management changed after the results of the DAT scan were obtained. The clinical diagnosis of drug-induced parkinsonism showed the best clinical accuracy because the diagnosis remained the same (i.e., drug induced) in 7 out of 8 cases after the DAT scan. Valproate contributed to 50% of the cases of drug-induced parkinsinosim and lithium contributed to 25% of clinically diagnosed drug-induced parkinsonism. However, one patient who was on valproate was found to have an abnormal DAT scan. He was started on levodopa and valproate was continued. Two of the patients with valproate-induced parkinsonism were taken off valproate; however, one had to continue the medication because his seizures were well-responsive to valproate.
DAT-SPECT scan supported 84% of the clinical diagnosis of degenerative parkinsonism by showing abnormal/positive results. Of those 21 patients showing positive results, 14 were diagnosed with IPD, 3 with progressive supranuclear palsy (PSP), 2 with multisystem atrophy (MSA), and 2 with Lewy body dementia More Details (LBD). The DAT scan changed the diagnosis in 4 patients who had a pre-scan diagnosis of degenerative parkinsonism. Three of them were diagnosed as having essential tremor and one as having drug-induced parkinsonism.
DAT scan is a helpful tool in distinguishing pre-synaptic parkinsonism [idiopathic Parkinson's disease (IPD), progressive supranuclear palsy (PSP), multi-system atrophy (MSA), and Lewy body dementia (LBD)] from post-synaptic parkinsonism (drug-induced parkinsonism, vascular parkinsonism). This can have a significant impact on the diagnosis and patient management. Our series showed a change in the diagnosis and management in 23% of patients; however, other studies have shown that there were more than 60% changes in the post-DAT scan diagnosis or management of patients.,
A search in the PubMed with keywords DAT, SPECT, and parkinsonism reveals more than 240 original articles, reviews, neuroimages, case reports, etc. The original articles and reviews from clinical and treatment standpoint can be categorized into two major groups, namely, diagnostic and clinical implications of DAT imaging and DAT scan, and studies on motor symptoms. These articles suggest that DAT scan can be helpful for the following:,,,,,,,
Till date, there is no convincing evidence that DAT scan can distinguish among various subtypes of degenerative parkinsonism such as IPD, MSA, progressive supranuclear palsy, corticobasal degeneration, and LBD.
As the major route of excretion of 123 Ioflupane is renal, the risk of radiation is high in patients with severe renal failure. Fortunately, there were no reported cases of acute kidney injury in our patients after the study. If the patient is very anxious, then a small dose of sedation is recommended in the standard practice guidelines; however, none of our patients needed sedation. DAT scan is usually very well-tolerated. The most widely reported adverse reactions directly related to DAT-SPECT scan in literature are headache and injection site pain.
There are emerging evidences that DAT scan can distinguish between tremor predominant Parkinson's disease and non-tremor predominant Parkinson's disease., There is a recent article that suggested that DAT imaging could help in predicting which groups of people were likely to develop levodopa-induced dyskinesia in the future. However, more robust evidence is required before such observations can be translated into clinical practice.
There is emerging evidence that DAT scan can be used to assess if non-motor symptoms have any correlation with dopamine loss in the brain.,,, Some studies revealed that apathy or depression in degenerative parkinsonism was contributed by dopamine transporter (DaT) loss in the brain.,
The major articles focusing on DAT SPECT imaging are given in [Table 5].
A study of DAT scan in the Cork University Hospital (CUH) by Corigan et al., revealed that 56.7% of the subjects were male, and that 66.8% of the scans were positive, and nearly 2% were equivocal. The mean age of the patients in the Cork series was 64.5 compared to 68 years in our study. Corrigan et al., found that patients below 60 years of age were more likely to show abnormal DAT imaging; however, we did not find any significant difference between patients below the age of 60 years and those above the age of 60 years. Our cohort showed that the General Practitioners (GPs) ordered 12% of scans whereas the Cork series revealed that GPs requested approximately 8% of all DAT scans.
Booij et al., demonstrated the effect of drugs such as modafinil, amphetamine, methylphenidate, fentanyl, phenylephrine bupropion, benzatropine, and cocaine upon the DAT scan in 2008. Their study recommended cessation of such drugs for at least 5 half-lives before the scan. Interestingly, antiparkinsonian drugs do not significantly affect tracer binding to DAT. The Society of Nuclear Medicine (SNM) consensus guidelines recommend a detailed drug history taking including that of the abovementioned drugs in every patient before DAT imaging. However, the FDA could not establish beyond doubt if these drugs interfered with DAT uptake. Nowadays, most European centres do not stop these drugs, except cocaine, before the scan.
However, for a history of drug intake such as cocaine, we had to rely on the patients' own history, family history, nursing input, as well as reports from the GP, local addiction centres, and of previous hospital admission records. A robust digital record keeping system and a well-defined geographical catchment area of our hospital makes these records easily obtainable from various sources. None of our patients used cocaine regularly, according to the abovementioned sources.
Only 3 of our requisition forms mentioned a history of head trauma, stroke, or neck deformity that could have interfered with the interpretation of the scan. Head tilt can make the DAT scan interpretation difficult. This is especially relevant because dyskinesia and dystonia can be associated with parkinsonism. As the basal ganglia image obtained in the DAT imaging is small, a minor head tilt can lead to misinterpretation of the normal (negative) scan as being falsely positive, sometimes termed as the “semicolon sign.” Janicek et al., reported a DAT imaging artifact because of continuous head rotation during the image acquisition known as the “pinwheel sign.”
Correlative brain imaging is not an absolute requirement for performing or reporting majority of DAT scans but sometimes can be helpful. Fearon et al., showed that the dilated Virchow Robin spaces could result in an abnormal DAT scan. A basal ganglia or a caudate infarct can make the interpretation of the DAT scan difficult, and hence a prior history of stroke should be made available for the proper interpretation of the scan.,
Obtaining an early diagnosis of Parkinsonism was the most common indication for DAT scan in our cohort. However, the outcome of the DAT scan (normal or abnormal) correlated best with clinical suspicion when the clinician ordered the scan to differentiate between drug-induced parkinsonism and IPD (nearly 87% accurate). DAT imaging changed the diagnosis in 63% cases, and mainly helped in differentiating IPD from drug-induced parkinsonism.
Many UK centres use DAT imaging to distinguish LBD from other forms of dementia because LBD constitutes up to 30% of all dementias and is responsible for significant clinical implications because many of the LBD patients can develop severe extrapyramidal side effects after the use of typical antipsychotics. A recent meta-analysis of 419 patients suggested a pooled sensitivity of 86.5% and a specificity of 93.6% for the differentiation of LBD from non-LBD disorders using 123I-FP-CIT SPECT scan. However, till date, our Nuclear Medicine Department has received no DAT request directly from the Psychiatry Department.
We recommended a follow-up for 6 patients with equivocal DAT images as Tolosa et al., suggested that a repeat scan after 2 years could increase the diagnostic yield to more than 87% in previously equivocal or inconclusive scans. The high cost of the DAT scan remains a major obstacle for a repeat imaging in our centre. However, one such patient had a repeat DAT scan that again showed equivocal result. This patient was ultimately clinically diagnosed to be having IPD.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]