Nuclear Imaging in the Diagnosis of Clinically Uncertain Parkinsonian Syndromes
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Background: Parkinsonian syndromes are classified by etiology mainly on clinical grounds, that is, on the basis of the clinical manifestations and with the aid of conventional ancillary studies. In most cases, the clinical diagnosis is clear. In up to 30% of cases, however, the etiological classification remains uncertain after completion of the basic clinical diagnostic evaluation, and additional investigation with nuclear imaging may be indicated. In particular, cerebral single-photon emission computed tomography (SPECT) with dopamine transporter (DAT) ligands may be helpful. DAT-SPECT can be used to demonstrate or rule out nigrostriatal degeneration and thereby differentiate neurodegenerative parkinsonian syndromes from symptomatic parkinsonian syndromes and other differential diagnoses. Positron emission tomography (PET) with the glucose analogue [18F]fluorodeoxyglucose (FDG) can be used to identify disease-specific patterns of neuronal dysfunction/degeneration in order to differentiate the various neurodegenerative parkinsonian syndromes from one another.
Methods: In this review, we summarize the current state of the evidence on DAT-SPECT and FDG-PET for the indications mentioned above on the basis of a selective review of the literature.
Results: DAT-SPECT has been adequately validated as an in vivo marker for nigrostriatal degeneration. Studies using the clinical diagnosis of a movement disorders specialist over the course of the disease as a reference have shown that DAT-SPECT is 78–100% sensitive (median, 93%) and 70–100% specific (median, 89%) for the differentiation of neurodegenerative parkinsonian syndromes from symptomatic parkinsonism and other differential diagnoses in clinically unclear cases. DAT-SPECT scanning led to a change of diagnosis in 27–56% of patients (median, 43%) and to a change of treatment in 33–72% (median, 43%). FDG-PET enables the differentiation of atypical neurodegenerative parkinsonian syndromes from the idiopathic parkinsonian syndrome (i.e., Parkinson’s disease proper) with high sensitivity and specificity (both approximately 90%), when the clinical diagnosis by a movement disorders specialist over the course of the disease is used as a reference.
Conclusion: DAT-SPECT has been well documented to be highly diagnostically accurate and to have a relevant influence on the diagnosis and treatment of patients with clinically uncertain parkinsonian or tremor syndrome. It has not yet been shown to improve patient-relevant endpoints such as mortality, morbidity, and health-related quality of life; proof of this will probably have to await the introduction of neuroprotective treatments. The current evidence for the high differential diagnostic accuracy of FDG-PET in neurodegenerative parkinsonian syndromes needs to be reinforced by prospective studies with neuropathological verification of the diagnosis.
The term “clinically uncertain parkinsonian syndrome” refers to symptom constellations with akinesia and at least one of the cardinal symptoms rigor, resting tremor, and postural instability (1). In addition to Parkinson’s disease (idiopathic parkinsonian syndrome, IPS) (2), the causes of parkinsonian syndromes include the atypical neurogenerative parkinsonian syndromes (APS) such as multiple system atrophy (MSA) (3), progressive supranuclear palsy (PSP) (e1), and corticobasal syndrome (CBS)—the latter of which neuropathologically often results from corticobasal degeneration (CBD) (e2). These have to be distinguished from symptomatic parkinsonian syndromes and other differential diagnoses. Symptomatic parkinsonian syndromes can develop as a result of structural brain lesions (ischemic, traumatic, tumor-related), medication effects, intoxication, as well as inflammatory and metabolic disorders. Of great importance in clinical practice is vascular parkinsonian syndrome in subcortical arteriosclerotic encephalopathy. The differential diagnoses include normal pressure hydrocephalus, essential tremor, and (rarely) dopa-responsive dystonia. The different symptomatic parkinsonian syndromes as well as the differential diagnoses require completely different therapeutic approaches, and early diagnosis is crucial. The early differential diagnosis of the neurodegenerative parkinsonian syndromes is also crucial for adequately patient-centered therapy. In IPS this means early medication treatment (e3) and, over the course of the illness, different pharmacological strategies in order to improve patients’ quality of life (e4, e5). Patients with APS have a much poorer prognosis and derive little benefit (MSA, PSP-P) or no benefit at all (CBS and PSP-RS) from dopamine substitution treatment (e6). The correct etiological classification is therefore important in order to advise patients from a sociomedical perspective and spare them from undergoing unhelpful treatment that potentially causes adverse effects while initiating adequate symptomatic treatment measures (e6).
The etiological classification of parkinsonian syndromes is done primarily on a clinical basis—that is, on the basis of symptoms and by using conventional additional investigations, such as cranial magnetic resonance imaging (MRI) in order to rule out structural lesions (1). In the setting of non-specialist care, the clinical IPS diagnosis is accurate in about 75%, when made by a movement disorder specialist the diagnosis is accurate in 80% at the initial examination and in about 85% during follow-up examinations (4). The clinical APS diagnosis is less accurate (e7, e8). These numbers demonstrate the need for additional investigations for the purpose of etiological classification in cases that are clinically uncertain.
The guideline “Idiopathic Parkinsonian Syndrome“ of the German Society of Neurology (DGN) and the Association of the Scientific Medical Societies in Germany (AWMF), which was updated in 2016, lists the following additional investigations:
- Cerebral single-photon emission computed tomography (SPECT) with tracers for the dopamine transporter (DAT) (“DAT-SPECT should be undertaken early on in the disease course to confirm nigrostriatal deficit in clinically uncertain parkinsonian or tremor syndromes”) and
- Cerebral positron emission tomography (PET) with the glucose analogue [18F]fluorodeoxyglucose (FDG) to detect neuronal dysfunction/degeneration (“FDG-PET can be used in selected cases for the best possible differential diagnostic classification of neurodegenerative parkinsonian syndromes, especially for the differentiation of atypical neurodegenerative parkinsonian syndromes from idiopathic parkinsonian syndrome”) (1).
This review article summarizes studies of DAT-SPECT and FDG-PET for the indications mentioned in the guideline. We included recent publications (“recent” is taken to mean the time period since 2015—that is, after the literature selection for evaluating nuclear imaging in the DGN/AWMF guideline). DAT-SPECT will be discussed in greater detail here than FDG-PET because of the stronger guideline recommendation. For [123I]metaiodobenzylguanidine scintigraphy of the noradrenergic innervation of the heart for the purpose of distinguishing MSA from IPS, the reader is referred to the pertinent review articles (5, e9).
DAT-SPECT in the diagnostic evaluation of parkinsonian syndromes
We conducted a literature search in PubMed, using the search term “ioflupane OR FP-CIT OR datscan OR DAT-scan OR β-CIT OR ([(dopamine transporter) OR DAT] AND [(single photon emission tomography) OR SPECT OR SPET])”, which yielded 2476 hits on 17 June 2019. Furthermore, we undertook a backward search on the basis of selected publications and a forward search on Web of Science.
IPS and APS are accompanied by the loss of dopaminergic neurons in the substantia nigra and its nerve endings in the striatum (nigrostriatal degeneration) (e10–e13). Symptomatic parkinsonian syndromes and the differential diagnoses mentioned above are as a rule not accompanied by nigrostriatal degeneration.
Reduced DAT availability in the striatum is an appropriate marker for nigrostriatal degeneration in IPS since the degeneration of dopaminergic nerve endings in the striatum is very pronounced even at the early disease stages (e14–e16). Compensatory downregulation of the DAT expression in the remaining nerve endings results in more pronounced striatal DAT loss (e17–e19). To differentiate parkinsonian syndromes with relevant nigrostriatal degeneration (IPS and APS) from parkinsonian syndromes without relevant nigrostriatal degeneration (symptomatic parkinsonian syndromes, differential diagnoses) on the basis of the availability of striatal DAT, the DAT ligand N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[123I] iodophenyl) nortropane ([123I]ioflupane, [123I]FP-CIT) has been licensed as a tracer for SPECT (6). No further DAT tracers for SPECT (e20–e24) have been licensed to date.
In order to assess the results of DAT-SPECT, visual interpretation of the image (without quantitative evaluation) is usually sufficient (10). Agreement between different readers is usually good or very good (11, e32, e33). The proportion of borderline findings is below 10% (12, e34). The direct comparison of DAT-SPECT and DAT-PET to detect nigrostriatal degeneration at the symptomatic stage of neurodegenerative parkinsonian syndromes does not show any practice-relevant inferiority for DAT-SPECT compared with DAT-PET, although PET provides superior image quality with respect to spatial resolution and statistical noise (13, e35, e36). The explanation is that motor symptoms in IPS become obvious only from a DAT loss of at least 50% in the posterior putamen (14), and this large effect can be detected reliably by using DAT-SPECT too (Figure 1).
Prospective studies of the diagnostic accuracy of DAT-SPECT in clinically uncertain parkinsonian or tremor syndromes with postmortem verification are lacking. Studies that used the clinical diagnosis made by movement disorder specialists during the course of the illness as a reference showed a sensitivity of 78–100% (median 93%, 18 studies, of which five were recent, including 1963 patients, eTable) and a specificity of 70–100% (median 89%). Some of these studies possibly underestimated the diagnostic accuracy of DAT-SPECT because of the limitations of the clinical diagnosis as standard of truth. This is supported by the fact that the accuracy of DAT-SPECT improves with increasing time to follow-up to obtain the clinical reference diagnosis (11), probably because the clinical diagnostic accuracy improves over time (4). This assumption is also supported by a longitudinal study in which DAT-SPECT after 36 months showed in only two out of 99 patients a discordant finding compared with DAT-SPECT at the start of the study (15). In an annual loss of striatal DAT of 5% (IPS) to 10% (APS) (16), DAT-SPECT after three years would have been able to detect nigrostriatal degeneration that at the time of the initial examination was below the detectability threshold (17). Uncertainty in determining the sensitivity of DAT-SPECT originates not least from the fact that some patients with a clinical diagnosis of a neurodegenerative parkinsonian syndrome present with normal DAT availability according to DAT-SPECT; these patients are referred to as “subjects without evidence of dopaminergic deficit (SWEDD)” (18). Longitudinal studies in which most of the SWEDD had a normal finding on DAT-SPECT even after two to five years hint at clinical overdiagnosis of neurodegenerative parkinsonian syndrome as the most likely explanation for SWEDD (15, 19, e37).
The Movement Disorder Society lists a normal result on DAT-SPECT as an absolute exclusion criterion for the diagnosis of clinically certain or possible IPS (2). A pathological DAT-SPECT result was not included as a supporting criterion for a diagnosis of IPS because DAT-SPECT is not suitable for differentiating IPS from APS (2). For the diagnosis of probable MSA of the cerebellar type a pathological DAT-SPECT result is one of six additional characteristics of which at least one has to be present (3).
After DAT-SPECT, the diagnosis changes in 27–56% of patients with clinically uncertain parkinsonian or tremor syndrome (median 43%, 12 original studies, of these 8 recent ones, including a total of 2719 patients) (Table). In 33–72% of patients, DAT-SPECT results in changing treatment (median 43%). In a clinically certain diagnosis of IPS, DAT-SPECT probably affects management much less than in clinically uncertain cases (20).
In sum, high diagnostic accuracy and a relevant effect on the diagnosis and therapy in clinically uncertain parkinsonian or tremor syndromes have been well confirmed as the basis of the guideline recommendations for DAT-SPECT; recent studies have added to the evidence (eTable, Table). The European IPS guideline recommends DAT-SPECT in the setting of significant diagnostic uncertainty, especially in atypical tremor manifestations (21). According to the British guideline, DAT-SPECT should be considered in case of uncertainty regarding the differentiation of parkinsonian syndrome with nigrostriatal degeneration and essential tremor (22).
Guideline recommendations for DAT-SPECT relate exclusively to clinically uncertain cases. A clinical uncertain parkinsonian or tremor syndrome is present if at least one of the following criteria is met (23, 24):
- Only one of the three cardinal symptoms rigor, resting tremor, postural instability in addition to akinesia/bradykinesia
- Two cardinal symptoms without akinesia/bradykinesia
- Atypical symptoms
- Only mild symptoms
- Poor response to dopamine substitution treatment
- Very slow/absent or very rapid progression of symptoms
- Atypical age.
The primary suspected diagnoses are immaterial: DAT-SPECT serves the purpose of differentiating parkinsonian syndromes with nigrostriatal degeneration (independently of the cause of the degeneration) from parkinsonian syndromes without nigrostriatal degeneration (also independently of the etiology) in clinically uncertain cases. Application of these criteria for a clinically uncertain parkinsonian or tremor syndrome (explicitly or mutatis mutandis) results in a pretest probability for pathological DAT-SPECT findings of 27–79% (median 60%, eTable). Clinical uncertainty regarding the differentiation between IPS and APS is not an indication for DAT-SPECT (23).
In 2015, about 10 000 DAT-SPECT investigations were carried out in Germany (25). Assuming that of these, 1000–2000 were conducted in the setting of suspected Lewy body dementia (eBox), this corresponds to 30% of all patients with new-onset parkinsonism (incidence 33/100 000 per year [e38]). This speaks in favor of adequate use of DAT-SPECT. However, the rate of patients referred for DAT-SPECT when newly presenting with parkinsonism varies strongly between different movement disorder specialists (e39, e40). Model-based analyses of the cost effectiveness of DAT-SPECT assume 20–30% of clinically uncertain cases among all patients with early stage parkinsonian syndrome (26, e41).
The relevant effect of DAT-SPECT in clinically uncertain parkinsonian or tremor syndromes lies in enabling earlier correct diagnosis. As a result, patients benefit from receiving adequate treatment about 1–2 years earlier compared to clinical diagnosis alone (26, e42, e43). In individual cases, however, the time to correct diagnosis of a neurodegenerative parkinsonian syndrome on clinical grounds can be more than 10 years (e44).
Confirmation of the benefit of DAT-SPECT in the diagnostic evaluation of clinically uncertain parkinsonian or tremor syndromes in terms of patient-relevant endpoints—such as mortality, morbidity, and health related quality of life—is pending (27) and will probably only become possible once neuroprotective therapies become available.
For predicting α-synuclein pathology syndrome in patients with idiopathic REM sleep behavior disorder, DAT-SPECT probably yields independent information beyond clinical parameters and other investigations (e45–e48). The prognostic value of DAT-SPECT at very early clinical stages—that is, before the occurrence of motor symptoms—has, however, not been definitively explored. Thus, routine clinical use of DAT-SPECT for this indication cannot be recommended at this time.
In Germany, DAT-SPECT using [123I]ioflupane is also licensed for distinguishing dementia with Lewy bodies from Alzheimer’s disease (eBox).
Ioflupane is a cocaine analogue with a high affinity for DAT (e49). For DAT-SPECT, the maximum administered dose is 0.325µg ioflupane, which occupies, at most, 1% of striatal DAT. Typical cocaine effects require at least 60% DAT occupancy to occur (e50).
Temporary adverse effects of a mild or moderate intensity—especially headache and nausea—affect a maximum of 4% of patients (28). In one of 1180 patients, limbic encephalopathy was diagnosed, with a possible causal association with a DAT-SPECT investigation conducted 81 days previously (28). No further indications of severe adverse effects have been documented (28).
Intravenous administration of the recommended amount of radioactivity of 180 MBq [123I]ioflupane (e51) leads to an effective radiation dose of 4.4 millisievert (mSv) (29). The mean effective dose from natural sources of radiation in Germany is 2.1 mSv per year (range 1–10 mSv). The primary risk associated with exposure to low doses of radiation is that of developing a radiation-induced tumor. In an effective radiation dose of 4.4 mSv at age 50 years or older, the lifetime risk of dying from tumor disease thus induced is below 1 : 5000. By comparison, the overall lifetime risk to die from cancer is about 1 : 5 (www.cancer.org/cancer/cancer-basics/lifetime-probability-of-developing-or-dying-from-cancer.html). The mean latency period between radiation exposure and the occurrence of an induced tumor is eight years for leukemia and thyroid cancer; for all other tumor diseases it is more than 10 years (www.bfs.de/DE/themen/ion/wirkung/krebs/einfuehrung/einfuehrung. html). By comparison, the median survival after a diagnosis of APS is 3–5 years (e52, e53).
Relevant medication interactions are rare for DAT-SPECT. Before the investigation, only substances with direct DAT inhibition have to be discontinued: cocaine, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, modafinil, diethylpropion, mazindol, phentermine, bupropion, venlafaxine, radafaxine, fentanyl, ketamine, isoflurane, and phenyl-cyclidine-piperidine (30). The antidepressants venlafaxine and bupropion are of particular practical relevance. Antipsychotics do not have any relevant effect on DAT-SPECT and therefore do not have to be discontinued (30, e54). Smoking does not affect DAT-SPECT either (e55).
Lesions in the striatum or brainstem result in a defect in striatal tracer uptake on DAT-SPECT, which depending on its location cannot be distinguished from the typical pattern of nigrostriatal degeneration (e59, e60) (Figure 2). In order to avoid a misinterpretation of vascular lesions as an indication of nigrostriatal degeneration, DAT-SPECT should be interpreted in tandem with up-to-date structural imaging, preferably cranial MRI (31).
DAT-SPECT is not suitable for differentiating the various neurodegenerative parkinsonian syndromes (IPS, MSA, PSP, CBD) from each other (9, e61). The guideline names cerebral PET scanning using the glucose analogue [18F]fluorodeoxyglucose (FDG) as the best modality for this purpose (1).
FDG-PET in the differential diagnostic evaluation of neurodegenerative parkinsonian syndromes
FDG-PET of the brain depicts the regional cerebral glucose metabolism, which is closely connected to neuronal activity (e62–e64). Thus, cerebral FDG-PET is a marker for regional neuronal dysfunction/degeneration. The strength of FDG-PET in the differential diagnostic evaluation of neurodegenerative parkinsonian syndromes lies in the identification of disease-specific patterns of findings on PET (Figure 3). To support the visual assessment of the PET images, voxel-based evaluations are used which compare the FDG-PET image of the patient with those of healthy persons voxel by voxel, in the simplest scenario by using z scores or t tests (e65, e66). The result of the voxel-based test can be superimposed on tomography sections (Figure 3). Voxel-based testing improves the accuracy of FDG-PET in detecting neurodegenerative disorders for inexperienced persons interpreting the findings as well as for experts (e67).
A recent meta-analysis of FDG-PET to distinguish APS (MSA, PSP, CBD) from IPS showed a sensitivity of 91% (95% confidence interval [72; 98]) and a specificity of 91% [70; 98] in relation to the clinical diagnosis made by movement disorder specialists after a period of 1–2 years after the PET investigation (32). At the time of the PET, the clinical diagnosis was usually uncertain (32). FDG-PET offered good accuracy for differentiating MSA from PSP and CBD (33). Differentiating PSP from CBD was less successful, in particular PSP was miscategorized as CBD (34), which is consistent with the wide overlap between the tauopathies PSP and CBD (e68–e71). New approaches to evaluating FDG-PET on the basis of voxel-based analysis of covariance allow for automatic and thus user-independent differentiation between the different neurodegenerative parkinsonian syndromes (35).
In view of the inherent uncertainties of the clinical differentiation of APS from IPS and APS among themselves, prospective studies with clinically relevant patient populations and postmortem verification of the diagnosis are needed for the further validation of FDG-PET for the differential diagnostic evaluation of neurodegenerative parkinsonian syndromes (38). Existing reports of case series with postmortem verification (35, e73–e77) are not sufficient, even though they confirm the disease-specific patterns of findings from patient populations with a clinical diagnosis.
Conflict of interest statement
Dr Buchert received financial support for conducting advanced training courses from GE Healthcare. He received study support from Pinax Pharma and Siemens. He received a honorarium from ABX-CRO for composing a manuscript.
Prof. Buhman received lecture fees from GE Healthcare.
Prof Meyer received travel expenses and lecture fees from GE Healthcare.
Prof. Gallinat received support for events or lectures from Lundbeck, Janssen-Cilag, Lilly, and Otsuka.
Dr. Apostolova declares that no conflict of interest exists.
Manuscript received on 1 March 2019, revised version accepted on
8 August 2019.
Translated from the original German by Birte Twisselmann, PhD.
Dr. rer. nat. Ralph Buchert
Klinik und Poliklinik für Diagnostische und Interventionelle Radiologie und
Nuklearmedizin, Universitätsklinikum Hamburg-Eppendorf
Martinistr. 52, 20246 Hamburg, Germany
Cite this as:
Buchert R, Buhmann C, Apostolova I, Meyer PT, Gallinat J: Nuclear imaging in the diagnosis of clinically uncertain parkinsonian syndromes. Dtsch Arztebl Int 2019; 116: 747–54. DOI: 10.3238/arztebl.2019.0747
For eReferences please refer to:
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Department of Neurology, University Medical Center Hamburg-Eppendorf: Prof. Dr. med. Carsten Buhmann
Department of Nuclear Medicine, Medical Center—University of Freiburg: Prof. Dr. med. Dr. nat. med. Philipp T. Meyer
Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf: Prof. Dr. med. Jürgen Gallinat
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