Neurology -- Correspondence for Ravina et al., 64 (2) 208-215

Correspondence published:

Reply to Zweig and Marshall: Bernard M Ravina, Nicholas Lange, Ken Marek, Robert Holloway, David Eidelberg (16 April 2005)

The role of radiotracer imaging in Parkinson disease: V L Marshall, Donald G Grosset (16 April 2005)

The role of radiotracer imaging in Parkinson disease: Richard M. Zweig, David L. Lilien, Kerrie Tainter, and James Patterson (16 April 2005)

Reply to Zweig and Marshall 16 April 2005

Bernard M Ravina,
Dept. of Neurology
University of Rochester, Town House, Mt. Hope Avenue, Rochester, NY 14620,
Nicholas Lange, Ken Marek, Robert Holloway, David Eidelberg
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Re: Reply to Zweig and Marshall

bernard.ravina{at}ctcc.rochester.edu Bernard M Ravina, et al.

We thank Dr. Zweig for his interest in our article. The recommendations made in the article addressed a range of uses of radio tracer imaging (RTI) in PD. [1] As we stated, the use of imaging as a diagnostic tool in PD is encouraging. We agree that RTI is able to detect clinically meaningful reductions in nigrostriatal dopaminergic function. However, RTI may not accurately discriminate between PD and other forms of degenerative parkinsonism. Studies addressing this issue are being conducted. [2]
The performance characteristics of both positive and negative tests should be considered as both results will be obtained in practice. Additionally, our recommendations were based on all of the published evidence. It is premature to draw broad conclusions about the negative and positive predictive values of RTI or any other imaging modality in degenerative forms of parkinsonism based on current data or experience in a single center. Positive and negative predictive values vary with the underlying prevalence of the disease, referral patterns for testing, and the intrinsic properties (sensitivity/specificity) of the test. The lower the underlying prevalence rate, the lower the positive predictive value. [3] Therefore, results reported from a single center may not be generalized. It is preferable to report predictive performance over a prevalence range. Careful interpretation of measures of prevalence (prior probability), likelihood ratio, and posterior probability combined across multiple studies will be needed to make generalizable statements about the diagnostic utility of RTI in PD.
The wide availability of RTI techniques speaks to the feasibility of its use as a diagnostic tool, but also underscores the need for appropriate studies before suggesting the use of RTI as a screening test. As we have seen with other diagnostic tests, the ultimate impact depends on a variety of factors including technical proficiency, receiver-operating characteristic (ROC) curves, and the clinical implications of the test results, specifically false positives and false negatives.
We also thank Drs. Marshall and Grosset for their interest in our article. The citation supporting the diagnostic sensitivity and specificity (98% and 83%, respectively) of B-CIT and SPECT for parkinsonism compared to patients with ET or healthy controls, is the Parkinson Study Group article of 2000. [4]
References
1. Ravina B, Eidelberg D, Ahlskog JE, et al. The role of radiotracer imaging in Parkinson disease. Neurology 2005:64;208-215.
2. Eckert T, Dhawan V, Frucht S, Gordon MF, Feigin AS, Eidelberg D. FDG PET in the differential diagnosis of parkinsonian disorders. NeuroImage (In press).
3. Hennenkens CH, Epidemiology in Medicine, Boston: Little Brown and Co, pp 336-449.
4. A multicenter assessment of dopamine transporter imaging with DOPASCAN/SPECT in parkinsonism. Parkinson Study Group. Neurology 2000:55;1540-1547.

The role of radiotracer imaging in Parkinson disease 16 April 2005

V L Marshall,
Institute of Neurosciences, Department of Neurology, Southern General Hospital
1345 Govan Road, Glasgow G51 4TF,
Donald G Grosset
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Re: The role of radiotracer imaging in Parkinson disease

v.marshall{at}clinmed.gla.ac.uk V L Marshall, et al.

Ravina et al performed a review of functional imaging as a marker of disease activity and progression and as a diagnostic tool in Parkinson�s disease. [1] Diagnostic sensitivity and specificity were incorrectly attributed to beta-CIT SPECT. They referred to work with the FP-CIT ligand. [2,3] This compounds a similar error in another recent review. [4] FP-CIT is licensed in Europe (DaTSCAN, GE Healthcare) for patients with clinically uncertain Parkinsonian syndromes to aid the differential diagnosis of Parkinson�s disease and tremor disorders, and has already been applied to several of the very valid questions raised in the article.
We agree that �most diagnostic studies have been small, single center studies of patients with probable Parkinson disease� but this statement omits the larger dual and multi-center studies with FP-CIT. One hundred and eighty-nine diagnostically uncertain Parkinsonian patients [2,5] have been specifically selected for study with FP-CIT. Our prospective study of 62 early and diagnostically uncertain cases reported with initial 3 months� follow-up [2] is ongoing. A further multi-center project shows increased congruence of the clinicians� diagnosis to the baseline FP-CIT SPECT image at 18 months, in 180 patients (European FP-CIT study group, unpublished observations).
In accordance with other neuroimaging studies when baseline FP-CIT SPECT showed normal results, this was reconfirmed at 18 months suggesting an alternative diagnosis than degenerative parkinsonism, and challenging concepts of low sensitivity of the technique in early disease. FP-CIT SPECT has already been shown to influence diagnosis and clinical management decisions, and we encourage further research.
References
1. Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M et al. The role of radiotracer imaging in Parkinson disease. Neurology 2005; 64(2):208-215.
2. Benamer HT, Oertel WH, Patterson J, Hadley DM, Pogarell O, Hoffken H et al. Prospective study of presynaptic dopaminergic imaging in patients with mild parkinsonism and tremor disorders: part 1. Baseline and 3-month observations. Mov Disord 2003; 18(9):977-984.
3. Benamer TS, Patterson J, Grosset DG, Booij J, de Bruin K, van Royen E et al. Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]- FP-CIT study group. Mov Disord 2000; 15(3):503-510.
4. Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet 2004; 363:1783-1793.
5. Catafau AM, Tolosa E, DaTSCAN Clinically Uncertain Parkinsonian Syndromes Study Group. Impact of dopamine transporter SPECT using 123I- Ioflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov Disord 2004; 19(10):1175-1182.
Dr. Grosset has received consultancy fees from GE Healthcare.

The role of radiotracer imaging in Parkinson disease 16 April 2005

Richard M. Zweig,
LSU Health Sciences Center - Shreveport
1501 King's Highway, Shreveport, LA 71130,
David L. Lilien, Kerrie Tainter, and James Patterson
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Re: The role of radiotracer imaging in Parkinson disease

rzweig{at}lsuhsc.edu Richard M. Zweig, et al.

While comprehensive, the recent review of the role of radiotracer imaging in Parkinson�s disease (PD) may be pessimistic about the future use of this technology. [1] The common dogma, based on imaging and pathological studies, that clinical symptoms do not appear until there is at least a 40 - 50% loss of dopaminergic input to the striatum, would suggest that the negative predictive value of a normal scan would approach 100%. This appears to have been the case in studies using [¹⁸F] fluorodopa (F-DOPA) PET or dopamine transporter (SPECT) markers as surrogate markers for disease progression or as a diagnostic tool in patients with clinically uncertain parkinsonian syndromes. [2,3] We are not aware of a single patient with a normal scan subsequently demonstrating clinical progression or autopsy findings consistent with PD, or a subsequent abnormal scan. While often clinically obvious, PD or other causes of presynaptic dopamine deficiency can be challenging to diagnose in some patients. One study using [¹²³I]-Ioflupane SPECT in clinically uncertain patients reported that imaging results lead to changes in clinical management (by neurologists) in 72% of the patients studied. [3]
The practicality of radiotracer imaging in PD, both for research studies and as a diagnostic tool, is limited by availability and cost. SPECT technology is widely available, and our recent analysis indicates that 97% of the United States population lives within 75 miles of a PET facility. [4] We have obtained highly discriminating F- DOPA PET images in subjects pre-treated with carbidopa and entacapone and scanned for 16 minutes starting 1 hr and 15 min following intravenous injection of 5 mCi F-DOPA. Scans are acquired in 3D mode on a GE Advance PET scanner, reconstructed using 3D FORE Iterative routines, and then converted to Analyze 7.5 format, imported into statistical parametric mapping, and spatially normalized into standardized stereotactic space for objective across-subject analyses. [5] We believe that with optimization of the methodology, the price per scan in today's dollar can be reduced to less than $1,000. At this cost, the negative predictive value of a normal scan might be useful not only for the movement disorders specialist, but also for the general neurologist and primary care physician. As indicated, a normal scan might be a cost-effective exclusion criteria in trials of neuroprotective agents that are currently in the planning stages.
References
1. Ravina B, Eidelberg D, Ahlskog JE, et al. The role of radiotracer imaging in Parkinson Disease. Neurology 2005;64:208-215.
2. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson�s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003;54:93-101.
3. Catafau AM, Tolosa E. Impact of dopamine transporter SPECT using 123I-ioflupane on diagnosis and management of patients with clinically uncertain parkinsonian syndromes. Mov Disord 2004;19:1175-1182.
4. Patterson J, Moseley M. How available is PET in the US? Nuc Med in Biol (in press).
5. Friston KJ, Holmes AP, Worsley KJ, et al. Statistical paramentric maps in functional imaging: a general linear approach. Human Brain Mapping 1995;2:189-210.