Dopamine transporter scanning in the evaluation of

Expert Review of Neurotherapeutics

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Dopamine transporter scanning in the evaluation of patients with suspected Parkinsonism: a casebased user’s guide Federico Rodriguez-Porcel, Sheheryar Jamali, Andrew P. Duker & Alberto J. Espay To cite this article: Federico Rodriguez-Porcel, Sheheryar Jamali, Andrew P. Duker & Alberto J. Espay (2016) Dopamine transporter scanning in the evaluation of patients with suspected Parkinsonism: a case-based user’s guide, Expert Review of Neurotherapeutics, 16:1, 23-29, DOI: 10.1586/14737175.2015.1120160 To link to this article: http://dx.doi.org/10.1586/14737175.2015.1120160

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Dopamine transporter scanning in the evaluation of patients with suspected Parkinsonism: a case-based user’s guide Expert Rev. Neurother. 16(1), 23–29 (2016)

Federico RodriguezPorcel1,2, Sheheryar Jamali1,2, Andrew P. Duker1,2 and Alberto J. Espay*1,2 1

Department of Neurology, UC Neuroscience Institute, University of Cincinnati, Cincinnati, Ohio, USA 2 Gardner Family Center for Parkinson’s Disease and Movement Disorders, Cincinnati, Ohio, USA *Author for correspondence: [email protected]

Given the wide range of manifestations of parkinsonism and its mimics, the diagnosis may remain elusive or be misattributed in some patients. Dopamine transporter (DAT) single photon emission computed tomography (SPECT) (DaTscan), an imaging technique that probes the integrity of the presynaptic nigrostriatal system, can be useful in the evaluation of clinically complex parkinsonian disorders in the appropriate context and when adequately interpreted. Pearls and pitfalls in the use of DaTscan for the differential diagnosis of parkinsonisms are reviewed using a case-based format. While the DaTscan is no replacement for a careful neurological examination in ascertaining the likelihood of Parkinson disease or other parkinsonisms in most clinical scenarios, it can be useful in the assessment of disorders where an abducting resting tremor, a prominent postural tremor, or incongruent features are not sufficiently clear on exam to distinguish neurodegenerative parkinsonism from dystonia, drug-induced parkinsonism and functional (psychogenic) parkinsonism, respectively. KEYWORDS: DaTscan

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drug-induced parkinsonism ● Parkinson disease ● parkinsonism ● SWEDD ● tremor

Dopamine transporter (DAT) single photon emission computed tomography (SPECT) (DaTscan) is an imaging technique that can probe the integrity of the presynaptic nigrostriatal system by capturing the uptake of the ligand 123-Ioflupane (123I-FP) in the putamen and caudate.[1] DaTscan can be useful in the evaluation of selected patients with parkinsonism, particularly to distinguish neurodegenerative parkinsonisms, which is most commonly represented by idiopathic Parkinson disease (PD), from drug-induced parkinsonism (DIP) and other PD-like disorders. The FDA approved DaTscan in 2011 to assist in distinguishing parkinsonian syndromes (PD, multiple system atrophy and progressive supranuclear palsy) from essential tremor.[2] While it is clear that the DaTscan is of no utility in distinguishing PD from atypical parkinsonisms with which it may be confused, it

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10.1586/14737175.2015.1120160

has become a useful technique to separate PD from selected PD mimics, namely DIP, dystonic tremor and functional (psychogenic) parkinsonism (FP).[3–5] We here provide a case-based approach to illustrate the pearls and (few) pitfalls associated with the clinical use of DaTscan. Case 1: pseudoparkinsonian resting and postural hand and jaw tremor

This 57-year-old woman presented with a 2.5year history of head tremor. She later developed bilateral hand tremor at rest, right foot tremor when driving, along with a chin and jaw tremor. She had been on lithium for bipolar disorder in the past, but this had been discontinued for at least 10 years. She had been on aripiprazole for 2 years, with no changes in the severity of the tremor. On examination, she had a position-dependent,

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predominantly resting and reemergent postural tremor, with involvement of the jaw. Sequence effect in finger tapping suggested bradykinesia (Video 1). Considered as a benign tremulous variant of PD, she was started on levodopa. After 4 months, the tremor in her jaw and head improved markedly, but there was minimal improvement in the hand tremor, despite increasing the dose significantly. On exam, her hand tremor showed dystonic features (Video 2). A trial of trihexyphenidyl was added to the levodopa regimen and a DaTscan ordered to determine the extent to which there was a presynaptic parkinsonism. DaTscan demonstrated normal radionuclide uptake in caudate and putamen bilaterally, making the diagnosis of PD less likely. However, given the clinical picture and the response to levodopa, the diagnosis of “benign tremulous PD” was held. One year after her initial diagnosis, her tremor almost completely normalized with the addition of trihexyphenidyl, beyond what had been accomplished with levodopa in the jaw and head tremor. Pitfall

The studies that validated the use of DaTscan as a tool to distinguish between parkinsonism and essential tremor used clinical examination (for the clinical diagnosis) and visual inspection (for the imaging diagnosis) as gold standards.[6,7] Some have suggested that the overall accuracy of DaTscan for parkinsonian syndromes is equal to but not better than the accuracy of a carefully obtained clinical diagnosis.[8] There are no studies correlating the diagnostic sensitivity and specificity of DaTscan with neuropathologic diagnosis. The role of levodopa response, on the other hand, in greatly increasing diagnostic accuracy is supported by clinicopathologic studies.[9] However, some cases of “benign tremulous PD” may indeed represent “essential tremor with a resting component” according to data from autopsy studies where 25% of these patients did not exhibit nigral pathology.[10] The lack of clinical progression in this case supports the possibility of a “true negative” DaTscan and raises the possibility that this patient has a PD-like dystonic tremor rather than a tremordominant form of PD (Figure 1).[11] Case 2: pseudoparkinsonian “resting” hand tremor

This 65-year-old woman had been diagnosed as PD after a 3-year history of progressive left-hand resting tremor. She had not required initiation of symptomatic dopaminergic treatment. Unusual historical features for PD included no micrographia, anosmia or constipation. On examination, her tremor was predominantly postural and position dependent. There was no rigidity, no decrement in amplitude during repetitive finger tapping and normal arm swinging (Video 3). DaTscan was ordered to resolve the uncertainty and support a tentative diagnostic revision to dystonic tremor. DaTscan demonstrated normal radionuclide uptake in caudate and putamen bilaterally, thus making PD unlikely and supporting the clinical diagnosis of dystonia, expressed as dystonic tremor. Antidystonic rather than antiparkinsonian treatment options were discussed. 24

Pearl

Misdiagnosis of PD is not uncommon.[12] Dystonic tremor is a relatively common PD mimic.[13] The PD-like tremor of dystonic tremor has been recognized in patients with suspected PD and scans without evidence of dopaminergic deficits (SWEDDs). SWEDD patients may account for up to 15% of clinical trial subjects, leading to inappropriate pharmacotherapy of patients and lower signal-to-noise ratio in studies, which then suffer from reduced power to find true differences. The use of DaTscan may become more common in selecting candidates for putative neuroprotective trials in PD and be proven costeffective if it helps decrease sample size by eliminating at least one source of diagnostic error (again keeping in mind that DaTscan will not distinguish PD from other PD-like neurodegenerative disorders). Case 3: very slow progression of “tremor-dominant parkinsonism”

This 66-year-old man presented with a 2.5-year history of worsening left-hand resting tremor eventually apparent during movements. He endorsed a long history of anosmia. On examination, he exhibited an asymmetric resting tremor, bradykinesia, rigidity, and ipsilateral decreased arm swing during walking, with preserved postural reflexes (Video 4). The diagnosis of PD was made, though no treatment was started given the mild intensity of his tremor. He agreed to participate in the Parkinson’s Progression Markers Initiative (PPMI) study, which included a DaTscan.[14] The DaTscan demonstrated normal radionuclide uptake in the caudate and putamen bilaterally, ruling out PD. As part of the study, he was evaluated every 6 months, reporting very mild interval worsening of his symptoms and modest deterioration of his motor scores on examination. DaTscan repeated after 2 years of follow-up, despite ongoing clinical suspicion for PD given the non-jerky nature of his tremor and lack of dystonic features, was again normal suggesting a non-PD tremor, possibly a form of essential tremor with prominent resting component or dystonic tremor with clinically suggestive features to be manifested belatedly. Regardless of the underlying etiology, the DaTscan was helpful in excluding PD in the face of clinical data (including the history of anosmia) sufficiently in favor of this neurodegenerative disorder. Pearl

Once methodological and interpretation issues are excluded, the presence of SWEDDs in a patient with a clinical diagnosis of parkinsonism should raise the suspicion of an alternate diagnosis. These patients often have mild symptoms, with tremor as the most salient feature, and tend to lack non-motor features of PD.[15] Patients with SWEDD typically have little benefit from levodopa.[16] Progression of symptoms is usually benign, though a small number of SWEDD patients (3%) have manifested a more overt parkinsonism.[17] Only about 10% of patients with SWEDD develop an abnormal DaTscan after a Expert Rev. Neurother. 16(1), (2016)


DaTscan in the evaluation of patients with suspected parkinsonism

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Figure 1. Diagnostic possibilities when considering a clinical presentation of tremor at rest. True bradykinesia is defined by the presence of a “sequence” effect, namely the progressive reduction of amplitude and/or speed with repetitive tasks, such as finger tapping.

period of 5–10 years.[5] This early false negativity is theorized to represent restricted PD pathology that falls below the resolution of this test. Case 4: parkinsonism and neuroleptic drug exposure—a coincidental relationship

This 73-year-old woman with a history of depression for 11 years had intermittent right-hand tremor when writing but not at rest, as well as difficulty standing from a seated position. She had been on aripiprazole since 2011 as adjunct treatment for depression. She endorsed anosmia and memory impairment for the past 2 years. Examination demonstrated www.tandfonline.com

impaired cognition (Montreal Cognitive Assessment = 18/30) with bradykinesia, intermittent rest and task-specific tremor, plus postural impairment (Video 5). While the history was suggestive of a neurodegenerative parkinsonism, possibly PD with dementia, the task-specific tremor was atypical for PD and the exposure to aripiprazole raised the possibility of DIP. DaTscan demonstrated normal uptake in both caudate nuclei but decreased uptake in the putamina. The findings ruled out DIP (where DAT binding is normal) and supported the diagnosis of neurodegenerative parkinsonism, potentially brought on or exacerbated by neuroleptic exposure. Symptomatic treatment with levodopa was initiated while aripiprazole was maintained at 25

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the request of her psychiatrist, with the possibility of replacing it with a non-neuroleptic medication in the near future.


Pearl

In clinically uncertain cases, where parkinsonism occurs in the background of exposure to neuroleptics, DaTscan can be helpful in distinguishing neurodegenerative parkinsonism from DIP and therefore informing therapeutic decisions. Patients suspected to have developed DIP who are documented to have a positive DaTscan likely represent subclinical PD (or other neurodegenerative parkinsonism) unmasked by neuroleptic medications.[3] Discontinuing the offending agent and observing over 6–12 months for changes in parkinsonian symptoms may suffice to clarify the diagnosis in mild cases, whereas long observation periods may be untenable in severe cases, such as the one discussed here, making DaTscan warranted. Anosmia and cognitive complaints were, in hindsight, important clues as to the neurodegenerative rather than iatrogenic nature of her parkinsonism. Case 5: parkinsonism and neuroleptic drug exposure—a causative relationship

This 67-year-old woman with a history of psychotic bipolar disorder developed right-hand tremor 9 years prior to her evaluation, which slowly became bilateral. Before the onset of her symptoms, she had been given valproate and risperidone in short sequence. Over the last year, she had started shuffling and falling. Her hand tremor had resting and postural components, and was interfering with her ability to feed and drink. Due to concerns for DIP, risperidone was replaced with lurasidone a month prior to her evaluation, to no avail. On examination, she had moderate bradykinesia, rigidity, slowed gait and impairment in postural reflexes (Video 6). Due to a long history of exposure to a variety of neuroleptics plus valproate, the diagnosis of DIP was felt to be most likely. However, the possibility of PD could not be excluded due to the asymmetry of presentation and the apparent acceleration of motor deficits. DaTscan showed normal ligand uptake in the caudate nuclei and putamina bilaterally, excluding PD and confirming DIP. Given the limited exposure to lurasidone, a newer antipsychotic with a theoretical better safety profile than others, we recommended discontinuing this drug only if no improvements were to become apparent within 3–4 months.[18] During this observation period, she steadily improved on lurasidone, and in 6 months she was walking normally and had only minimal residual hand tremor (Video 7).

Case 6: disproportionate disability in “PD”

This 37-year-old man had a progressive right-hand tremor at rest for 3 years. He also reported dragging of the right foot, memory loss and postural lightheadedness, and had mild truncal dyskinesia presumably in response to a combined treatment with benztropine and ropinirole, which otherwise provided only mild benefits. On exam, he showed a unilateral resting tremor and asymmetric bradykinesia and decreased arm swinging, in the absence of atypical motor features (Video 8). Our working diagnosis was early-onset Parkinson’s disease. Ropinirole was increased and benztropine discontinued. Over the following 2 years, he developed multiple syncopal episodes of unclear nature, paroxysmal diaphoresis, even when sitting, excessive fatigue, spells of coughing and choking of unclear etiology, and urinary and bowel incontinence. Maximization of ropinirole was of no help. A tilt table test was reported as normal. On a follow-up examination, he was found to have no rigidity when fully relaxed and no “true” bradykinesia, defined as the progressive reduction of amplitude (sequence effect) with repetitive tapping tasks. Despite a wide-based gait, he had a normal stride and intact ability to tandem walk and pivot. He showed excessive startle on the pull test (Video 9). This raised the concern for psychogenic parkinsonism. A DaTscan was ordered given this new appearance of incongruent clinical features disproportionate to what would have been expected for early-onset Parkinson’s disease, with acceleration of disability accrual. A diagnostic revision to FP was not yet warranted given the possibility that his clinical picture represented, at the core, mild neurodegenerative parkinsonism that was being embellished. The DaTscan demonstrated normal radionuclide uptake in the caudate and putamen bilaterally, supporting the clinical diagnosis of FP. Pearl

FP is a rare presentation of a functional movement disorder that represents a diagnostic challenge.[19] These patients usually present abruptly with maximal deficits at onset but minimal progression over time, and a tremor that can be entrained or at least dampened with concentration.[19] These features were absent in our patient. Nevertheless, his early response to dopaminergic medications was quite impressive and falsely reassured us in favor of PD. Remarkably, this patient exhibited mild truncal swaying, which was misinterpreted as drug-induced dyskinesia, albeit from ropinirole rather than levodopa, likely an early unrecognized functional feature. The DaTscan was helpful in revising the clinical diagnosis to FP and radically reconfiguring his management.[20]

Pearl

Case 7: “PD” by imaging but not on clinical examination

Given the appearance of parkinsonism within the context of chronic antipsychotic use, the accrual of deficits over several years and the lack of prompt benefit after switching to a “safer” drug, the case for PD was sufficiently robust to warrant a DaTscan. Had the DaTscan not been obtained and the diagnosis of unmasked PD assumed, a trial of levodopa would have seemed appropriate, when in fact it was not necessary.

This 74-year-old man presented with a 10-year history of progressive right-hand tremor, later affecting his left hand. His children had noticed head tremor since his 40s. Initially diagnosed as essential tremor, primidone had provided mild benefits, while topiramate was not useful. After a trial of levodopa provided some benefit, he had been on increasing doses of this medication with mild improvement, followed by transient

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Figure 2. DaTscan shows a tilted view of the striata, leading to misinterpretation of the study as suggestive of striatal denervation. On closer scrutiny, the patient had no evidence of true bradykinesia and had not evolved in a manner expected for a neurodegenerative parkinsonism, which prompted a second look at the scan and the contribution of the head tilt on the apparent asymmetry of the dopamine uptake was appreciated.

worsening when the dose was decreased. On exam, he had asymmetric hand tremor, on posture and action greater than at rest, with associated mild left torticollis and laterocollis, dystonic head tremor and spasmodic dysphonia (Video 10), suggestive of adult-onset cervical dystonia with segmental spread to the laryngeal and brachial regions. Given the absence of features suggestive of parkinsonism, we suspected he had a dystonic tremor with an unusual response to levodopa. A DaTscan obtained elsewhere had been interpreted as abnormal, with decreased uptake in the left striatum (Figure 2). However, after close examination, it was determined that the scan was tilted and the degree of uptake was considered within the normal range. Levodopa was later stopped without any worsening in the tremor. Pearls and pitfalls

This patient presents several learning points in clinical assessment and imaging interpretation. Primary adult onset dystonia may closely resemble tremor-dominant PD. These patients usually present with an asymmetric resting arm tremor, with impaired arm swing and even facial hypomimia or jaw tremor, but without true akinesia or sequence effect (progressive decrement of speed and amplitude on tapping tasks).[13] In terms of the imaging interpretation, inspection of the visual images may be misleading due to movement of the patient during the scan or head tilt, known as the “semicolon sign”. [21,22] Other sources of misinterpretation include the decrease in striatal uptake with age and the subtle anatomical asymmetries observed in healthy controls.[23,24] Finally, in cases like ours (and despite a subjective levodopa response), a DaTscan may not be warranted. In hindsight, the clinical findings alone should have sufficed to inform a management strategy for dystonic rather than parkinsonian tremor. Levodopa may indeed be helpful in some patients with focal dystonia and may be continued if symptomatic benefits are objectively measurable. Expert commentary and 5-year view

The wide phenotypic spectrum in PD and other neurodegenerative parkinsonisms may pose a challenge even to the

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experienced clinician. The identification of SWEDD in patients initially diagnosed as PD, representing about 15% patients enrolled in clinical trials, highlights the utility of DaTscan in diagnostically challenging parkinsonian or pseudoparkinsonian disorders.[25,26] The use of DaTscan will minimize false-positive PD diagnoses and substantially improve the signal-to-noise ratio. Moreover, its incorporation into biomarker development studies and clinical trials may serve to decrease the sample size.[21,25,27] While the sensibility and specificity of the DaTscan have been validated against the clinical assessment, and no pathologic confirmation studies have been published, long-term follow-up of DaTscan-negative “PD” patients continue to support its value as ancillary to the neurological assessment in selected cases. Given that DaTscan assesses the integrity of the presynaptic nigrostriatal dopaminergic fibers, it is of limited to no utility in distinguishing between various forms of neurodegenerative parkinsonism. The visual interpretation of the images should also account for the effects of head tilt, movement during the scanning procedure, loss of DAT receptor density with age and the effect of certain drugs on the dopamine uptake when formulating a report.[28] Drugs that bind to the DAT with high affinity may interfere with the image obtained following DaTscan administration. These include amoxapine, amphetamine, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, phenylpropanolamine, selegiline and sertraline. Selective serotonin reuptake inhibitors (e.g., paroxetine and citalopram) may increase or decrease ioflupane binding to the DAT and some centers advocate for their discontinuation at least 2 weeks prior to the procedure. Finally, quantitative evaluation of dopamine transport uptake data is desirable but remains unavailable at many centers. Adequate candidates for DaTscan are patients with atypical presentations of dystonic tremor, DIP and FP which may be difficult to distinguish from neurodegenerative parkinsonism. However, as some of the cases discussed demonstrated, a thorough neurological examination (sometimes in hindsight) is most critical in clarifying many clinical scenarios without the need for a DaTscan.

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Financial & competing interests disclosure AP Duker has served as a consultant for Merz Pharmaceuticals, US World Meds and Auspex Pharmaceuticals and received honoraria from UCB. AJ Espay is supported by the K23 career development award (NIMH, 1K23MH092735); has received grant support from CleveMed/Great Lakes Neurotechnologies, and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Chelsea Therapeutics, TEVA, Impax, Merz, Pfizer, Acadia, Cynapsus, Solstice Neurosciences, Eli Lilly, Lundbeck, and

USWorldMeds; royalties from Lippincott Williams & Wilkins and Cambridge University Press; and honoraria from UCB, TEVA, the American Academy of Neurology, and the Movement Disorders Society. He serves as Associate Editor of the Journal of Clinical Movement Disorders and on the editorial boards of Parkinsonism and Related Disorders and The European Neurological Journal. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


Key Issues ●

DaTscan assesses the concentration of dopamine transporter in the presynaptic nigrostriatal fibers by capturing the uptake of ligand 123-Ioflupane in the putamen and caudate.

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DaTscan can assist in the evaluation of selected patients with pseudoparkinsonian presentations of dystonic tremor, drug-induced parkinsonism and functional parkinsonism.

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Studies validating DaTscan have used expert clinical judgment as the gold standard. Nevertheless, a small postmortem study demonstrated a robust correlation between DaTscan abnormalities and substantia nigra cell loss.[29]

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Patients with a clinical diagnosis of tremor-dominant PD with mild symptoms, benign course, poor or equivocal response to levodopa and lack of (or unusual) progression should raise the suspicion of an alternate diagnosis such as dystonic tremor. DaTscan can be useful in clarifying the diagnosis.

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Interpretation of the scan should take into account potential confounders, such as aging, dopamine transporter–interfering drugs and technical issues, including head tilt and movement artifact.

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DaTscan is capable of distinguishing patients with PD from normal subjects even in the absence of symptoms. This feature might be useful in future biomarker and prodromal therapeutic studies.

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Supplementary material available online Videos 1 – 10 (http://dx.doi.org/10.1586/14737175.2015.1120160)

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