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• Incorrect trial number; correct number is NCT00368199
  Wim E.J. Weber
  Published on: 24 March 2016
• Re:Response to "Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients"
  Wim E.J. Weber
  Published on: 23 November 2015
• Response to "Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients"
  Philipp Mahlknecht
  Published on: 23 November 2015

• Published on: 24 March 2016

  Incorrect trial number; correct number is NCT00368199

  • Wim E.J. Weber, Consultant neurologist

  Our paper has the trial number NCT0036819, and it should read NCT00368199 (See https://clinicaltrials.gov/ct2/show/NCT00368199).

  Conflict of Interest:

  None declared

  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:Response to "Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients"

  • Wim E.J. Weber, Associate Professor
  • Other Contributors:
    • Angela Bouwmans, Annemarie Vlaar, Werner Mess, Alfons Kessels

  We would like to thank drs Mahlknecht, Seppi, and Berg for compliments on a study well designed and executed.

  They do, however, raise two major and one minor criticism to our study.

  Firstly, the DAT-SPECT data in our study were not in accordance with the clinical data, suggesting 'that clinical classification of the patients was suboptimal'. Secondly, the TCS data were disappointing, because, among o...

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  We would like to thank drs Mahlknecht, Seppi, and Berg for compliments on a study well designed and executed.

  They do, however, raise two major and one minor criticism to our study.

  Firstly, the DAT-SPECT data in our study were not in accordance with the clinical data, suggesting 'that clinical classification of the patients was suboptimal'. Secondly, the TCS data were disappointing, because, among other considerations, 'the authors had more problems in scanning with this machine than other groups'. Thirdly, our study results do not accord with current guidelines.

  1. We disagree with their statement that DAT-SPECT should have a specificity close to 100% in differentiating neurodegenerative parkinsonian syndromes such as Parkinson's disease (PD) and atypical parkinsonian disorders (APD) . They cite 2 studies [1,2] to support this, but this is not a representative sample of the complete literature. A meta -analysis of all published studies showed that our DAT-SPECT data generally do not differ from other studies: there are substantial numbers of early stage PD patients with a normal SPECT scan [3]. We thus do not think that our clinical diagnosis was compromised.

  Mahlknecht et al feel that 'such diagnostic accuracy data suggest not to use DAT-SPECT in the diagnostic work-up of patients presenting with a parkinsonian syndrome of recent onset which is against current recommendations'. We think that recommendations in themselves are not a valid argument in this discussion (See below), and, as we explicitly stated in our paper, our gold standard diagnosis of PD was a clinical one. For this clinical diagnosis we used the UK Brain Bank criteria, as also proposed by the EFNS guideline, of which both Daniela Berg and Klaus Seppi are co-authors [6].

  Additionally, as Mahlknecht et al suggested, we have recalculated the diagnostic accuracy of TCS in the subjects, whose final clinical diagnosis was also 'supported' by their DAT-scan. TCS was positive in 35% and negative in 65%. Diagnostic accuracy did thus not improve.

  2. We do not think that our sonographers would be less competent than others. One of us (WM) is an internationally recognised sonography expert, who had done additional training with Daniela Berg in T?bingen, especially for this project. We also did an interobserver study to assure reliability of our sonographies [4]. Up till this study our TCS results accorded with those reported in the literature [5]. We thus think that our TCS competency is in line with others.

  TCS diagnostic accuracy in early stage parkinsonian syndromes is simply absent in a carefully executed prospective study.

  In response to Mahlknecht et al that there are more prospective studies: we would like to point out that ours was the only one with this specific research question that was prospectively registered.

  As we reported in the earlier paper, newer ultrasound systems will reveal hyperechointensity of the SN in more patients [5], but it remains to be seen whether that will increase diagnostic accuracy, since this enhanced sensitivity migh decrease specificity.

  3. Mahlknecht et al are concerned that our data do not accord with guidelines for the use of DAT-SPECT and TCS [6-7]. We are sorry that our results do not support these guidelines, but fail to see how that would invalidate our data. Guideline development is not a scientifically impartial process and frequently biased by conflicts of interest [8].

  We do agree with Mahlknecht's final conclusion that, when studying TCS, careful consideration should be given to the way methods are applied and data are analysed.

  The conclusion of our earlier meta-analysis is still true: the clinical significance of substantia nigra hyperecho-intensity remains unclear [9].

  References 1. Marshall VL, Reininger CB, Marquardt M. Parkinson's disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT. Mov Disord 2009;24:500-8. 2. Jennings DL, Seibyl JP, Oakes D, Eberly S, Murphy J, Marek K. (123I) beta-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch Neurol 2004;61:1224-9. 3. Vlaar AM, van Kroonenburgh MJ, Kessels AG, et al. Meta-analysis of the literature on diagnostic accuracy of SPECT in parkinsonian syndromes. BMC Neurol 2007;7:27 4. Vlaar A, Tromp SC, Weber WE, Hustinx RM, Mess WH. The reliability of transcranial duplex scanning in parkinsonian patients: comparison of different observers and ultrasound systems. Ultraschall Med. 2011 Jan;32 Suppl 1:S83-8. 5. Vlaar AM, de Nijs T, van Kroonenburgh MJ et al. The predictive value of transcranial duplex sonography for the clinical diagnosis in undiagnosed parkinsonian syndromes: comparison with SPECT scans. BMC Neurol 2008;8:42. 6. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease. Eur J Neurol 2013;20:16-34. 7. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:968- 75. 8. Holloway RG, Mooney CJ, Getchius TS, Edlund WS, Miyasaki JO. Invited Article: Conflicts of interest for authors of American Academy of Neurology clinical practice guidelines. Neurology. 2008 Jul 1;71(1):57-63. 9. Vlaar AM, Bouwmans A, Mess WH, Tromp SC, Weber WE. Transcranial duplex in the differential diagnosis of parkinsonian syndromes: a systematic review. J Neurol. 2009 Apr;256(4):530-8.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Response to "Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients"

  • Philipp Mahlknecht, Resident
  • Other Contributors:
    • Klaus Seppi and Daniela Berg

  The study by Bouwmans and colleagues seems to be well designed and thoroughly executed [1], but the primary results are surprising regarding both the transcranial sonography (TCS) and dopamine transporters - single- photon emission computed tomography (DAT-SPECT) results. According to large scale prospective studies, DAT-SPECT should have a specificity close to 100% in differentiating neurodegenerative parkinsonian syndrom...

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  The study by Bouwmans and colleagues seems to be well designed and thoroughly executed [1], but the primary results are surprising regarding both the transcranial sonography (TCS) and dopamine transporters - single- photon emission computed tomography (DAT-SPECT) results. According to large scale prospective studies, DAT-SPECT should have a specificity close to 100% in differentiating neurodegenerative parkinsonian syndromes such as Parkinson's disease (PD) and atypical parkinsonian disorders (APD) based on the underlying nigrostriatal dopaminergic depletion versus other conditions without nigrostriatal denervation [2,3]. In this study specificity for PD was 68% and if merging the conditions which should not be associated with nigrostriatal denervation (i.e. the groups essential tremor, vascular parkinsonism, drug induced parkinsonism, and no parkinsonism) it still was only 84%. Sensitivity of DAT-SPECT to diagnose neurodegenerative parkinsonism was 88% for PD and 84% for neurodegenerative parkinsonism (i.e. merging the groups PD, multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies, and corticobasal degeneration) which is the range of the reported sensitivity in literature. However, considering that DAT-SPECT should detect neurodegenerative parkinsonian disorders in general, the negative predictive value was only 74% due the high false negative rate misclassifying subjects with a neurodegenerative process as having one of the other conditions. Such diagnostic accuracy data suggest not to use DAT -SPECT in the diagnostic work-up of patients presenting with a parkinsonian syndrome of recent onset which is against current recommendations [4,5]. Similarly, the TCS data in this study have determined suboptimal diagnostic accuracy in detecting PD. Up to now several independent studies by various groups have detected substantia nigra (SN) hyperechogenicity in 80-90% of patients with PD [6-13]. Depending on the cut-off, approximately 10% of healthy adult controls and patients with APDs and a slightly higher number of patients with ET have been reported to show SN hyperechogenicity [6,14-17]. It is unclear, why both the TCS and DAT-SPECT results in this study were surprisingly disappointing. Regarding the TCS data, one has to consider that insufficient technical equipment may have played a role; the authors used the Sonos 5500 Philips machine, which they had judged to be insufficient to display SN- hyperechogenicity in an earlier analysis of the baseline data ("Fourthly, the quality of the ultrasound system is a non-neglectable variable, since in our pilot examinations, we found that the newest ultrasound systems will reveal hyperechointensity of the SN in more patients...") [18]. However, the Sonos 5500 Philips machine has also been used by other groups, yielding useful images suitable for further statistical analysis. It is well known that the way settings are adjusted do play a major role for the visibility of structures under investigation. It cannot be estimated why the authors had more problems in scanning with this machine than other groups. Still, it needs to be acknowledged, that they realized themselves, that they would have done better with another device [18]. The main reason given by the authors for their discrepant results to the literature is that they postulate that their study is the second prospective after the study by Gaenslen et al. [20]. However, there are several other prospective studies in this field, showing the diagnostic utility of TCS in PD, APDs and essential tremor [6,17,22-24]and in the assessment of PD risk in rapid eye movement sleep behaviour disorder patients[25] as well as the general population [26]. Also recent guidelines from the EFNS/MDS-ES recommend TCS for the differential diagnosis of PD from APS and secondary parkinsonian syndromes, for the early diagnosis of PD, and for the detection of subjects at risk for PD [27]. As DAT-SPECT data are not in accordance with the clinical data, clinical classification of the patients might have been suboptimal. Other studies used DAT-imaging in addition to the clinical information to reach a final diagnosis and it would be interesting to know the diagnostic accuracy of TCS in the subjects, whose final clinical diagnosis was also supported by their DAT-Scan. Taken together, this study proves the importance of a good gold standard for diagnosis of all disease entities investigated in studies trying to validate other diagnostic instruments. Moreover, careful consideration should be given to the devices used and to the way methods are applied and data are analysed.

  Affiliations: Department of Neurology, Innsbruck Medical University (Philipp Mahlknecht and Klaus Seppi) Center of Neurology, Department of Neurodegeneration and Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany (Daniela Berg)

  References 1. Bouwmans AE, Vlaar AM, Mess WH, Kessels A, Weber WE. Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients. BMJ Open 2013;3. doi:pii: e002613. 10.1136/bmjopen-2013-002613. 2. Marshall VL, Reininger CB, Marquardt M. Parkinson's disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT. Mov Disord 2009;24:500-8. 3. Jennings DL, Seibyl JP, Oakes D, Eberly S, Murphy J, Marek K. (123I) beta-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch Neurol 2004;61:1224-9. 4. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:968- 75. 5. Pahwa R, Lyons KE. Early diagnosis of Parkinson's disease: recommendations from diagnostic clinical guidelines. Am J Manag Care 2010;16 Suppl:94-9. 6. Stockner H, Sojer M, Seppi K. Midbrain sonography in patients with essential tremor. Mov Disord 2007;22:414-7. 7. Ressner P, Skoloudik D, Hlustik P, Kanovsky P. Hyperechogenicity of the substantia nigra in Parkinson's disease. J Neuroimaging 2007;17:164-7. 8. Huang YW, Jeng JS, Tsai CF, Chen LL, Wu RM.Transcranial imaging of substantia nigra hyperechogenicity in a Taiwanese cohort of Parkinson's disease. Mov Disord 2007;22:550-5. 9. Walter U, Wittstock M, Benecke R, Dressler D. Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson's disease. J Neural Transm 2002;109:191-6. 10. Berg D, Siefker C, Becker G. Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings. J Neurol 2001;248:684-9. 11. Kolevski G, Petrov I, Petrova V. Transcranial sonography in the evaluation of Parkinson disease. J Ultrasound Med 2007;26:509-12. 12. Kim JY, Kim ST, Jeon SH, Lee WY. Midbrain transcranial sonography in Korean patients with Parkinson's disease. Mov Disord 2007;22:1922-6. 13. Okawa M, Miwa H, Kajimoto Y, et al. Transcranial sonography of the substantia nigra in Japanese patients with Parkinson's disease or atypical parkinsonism: clinical potential and limitations. Intern Med 2007;46:1527- 31. 14. Berg D, Becker G, Zeiler B, et al. Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology 1999;53:1026-31. 15. Berg D, Behnke S, Walter U. Application of transcranial sonography in extrapyramidal disorders: updated recommendations. Ultraschall Med 2006;27:12-9. 16. Berg D. Transcranial sonography in the early and differential diagnosis of Parkinson's disease. J Neural Transm Suppl 2006;249-54. 17. Mahlknecht P, Seppi K, Stockner H. Substantia Nigra Hyperechogenicity as a Marker for Parkinson's Disease: A Population-Based Study. Neurodegener Dis 2013;18. [Epub ahead of print] 18. Vlaar AM, de Nijs T, van Kroonenburgh MJ et al. The predictive value of transcranial duplex sonography for the clinical diagnosis in undiagnosed parkinsonian syndromes: comparison with SPECT scans. BMC Neurol 2008;8:42. 19. Hagenah J, K?nig IR, Sperner J et al. Life-long increase of substantia nigra hyperechogenicity in transcranial sonography. Neuroimage 2010;51:28- 32. 20. Mehnert S, Reuter I, Schepp K et al. Transcranial sonography for diagnosis of Parkinson's disease. BMC Neurol 2010;10:9. 21. Gaenslen A, Unmuth B, Godau J, et al. The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study. Lancet Neurol 2008;7:417-24. 22. Walter U, Dressler D, Wolters A, Probst T, Grossmann A, Benecke R. Sonographic discrimination of corticobasal degeneration vs progressive supranuclear palsy. Neurology 2004;63:504-9. 23. Walter U, Dressler D, Probst T, et al. Transcranial brain sonography findings in discriminating between parkinsonism and idiopathic Parkinson disease. Arch Neurol 2007;64:1635-40. 24. Behnke S, Hellwig D, B?rmann J, et al. Evaluation of transcranial sonographic findings and MIBG cardiac scintigraphy in the diagnosis of idiopathic Parkinson's disease. Parkinsonism Relat Disord 2013 Jul 20. [Epub ahead of print]. 25. Iranzo A, Lome?a F, Stockner H, et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol 2010;9:1070-7. 26. Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons. Berg D, Seppi K, Behnke S, et al. Arch Neurol 2011;68:932-7. 27. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease. Eur J Neurol 2013;20:16-34.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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