Journal of Neurology

, Volume 262, Issue 2, pp 346–356 | Cite as

Ancillary investigations to diagnose parkinsonism: a prospective clinical study

  • M. B. Aerts
  • R. A. J. Esselink
  • W. F. Abdo
  • F. J. A. Meijer
  • G. Drost
  • N. Norgren
  • M. J. R. Janssen
  • G. F. Borm
  • B. R. BloemEmail author
  • M. M. Verbeek
Original Communication


Various ancillary investigations can assist clinicians in the differential diagnosis of patients with parkinsonism. It is unknown which test offers greatest diagnostic value in clinical practice. We included 156 consecutive patients with parkinsonism, but with an initially uncertain diagnosis. At baseline, all patients underwent extensive clinical testing and the following ancillary investigations: brain magnetic resonance imaging (MRI); 123I-iodobenzamide single photon-emission computed tomography (IBZM-SPECT); analysis of cerebrospinal fluid (CSF); and anal sphincter electromyography (EMG). The final diagnosis was established after 3-year follow-up by two movement disorder specialists, according to international consensus criteria. We determined the diagnostic value by comparing the baseline clinical parameters and ancillary studies with the final diagnosis. Out of a potential 138 parameters, univariate analysis identified 35 parameters that discriminated Parkinson’s disease (PD, n = 62) and atypical parkinsonism (AP, n = 94), with AUC of 0.55–0.81. Stepwise logistic regression showed that the combination of tandem gait, axial UPDRS subscore, slow saccadic eye movements and dysphagia yielded an AUC of 0.93, adjusted for optimism. The combination of tandem gait and axial UDPRS subscore yielded an AUC of 0.90. None of the ancillary investigations alone or in combination with clinical testing improved this clinically based diagnostic accuracy, not even in a subgroup of patients with the greatest diagnostic uncertainty at baseline. Our study demonstrates that a comprehensive set of clinical tests provides good accuracy to differentiate PD from AP. Our results also suggest that routine MRI, IBZM-SPECT, CSF analysis and anal sphincter EMG do not improve this diagnostic accuracy. Future work should evaluate the possible diagnostic value of more advanced diagnostic tests.


Parkinson's disease Parkinsonism Cerebrospinal fluid MRI SPECT Multiple system atrophy Clinimetry Progressive supranuclear palsy Corticobasal syndrome Dementia with Lewy bodies EMG 



We thank the technicians of the departments of Laboratory Medicine, Radiology, Nuclear Medicine and Neurology for their work.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

415_2014_7568_MOESM1_ESM.docx (380 kb)
Supplementary material 1 (DOCX 380 kb)


  1. 1.
    Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ (2002) The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain J Neurol 125(Pt 4):861–870CrossRefGoogle Scholar
  2. 2.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, Goetz CG, Golbe LI, Grafman J, Growdon JH, Hallett M, Jankovic J, Quinn NP, Tolosa E, Zee DS (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47(1):1–9CrossRefPubMedGoogle Scholar
  4. 4.
    Litvan I, Goetz CG, Jankovic J, Wenning GK, Booth V, Bartko JJ, McKee A, Jellinger K, Lai EC, Brandel JP, Verny M, Chaudhuri KR, Pearce RK, Agid Y (1997) What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study. Arch Neurol 54(8):937–944CrossRefPubMedGoogle Scholar
  5. 5.
    Mahlknecht P, Hotter A, Hussl A, Esterhammer R, Schocke M, Seppi K (2010) Significance of MRI in diagnosis and differential diagnosis of Parkinson’s disease. Neurodegener Dis 7(5):300–318. doi: 10.1159/000314495 CrossRefPubMedGoogle Scholar
  6. 6.
    Vlaar AM, de Nijs T, Kessels AG, Vreeling FW, Winogrodzka A, Mess WH, Tromp SC, van Kroonenburgh MJ, Weber WE (2008) Diagnostic value of 123I-ioflupane and 123I-iodobenzamide SPECT scans in 248 patients with parkinsonian syndromes. Eur Neurol 59(5):258–266. doi: 10.1159/000115640 CrossRefPubMedGoogle Scholar
  7. 7.
    Hall S, Ohrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F, Nilsson C, Hakan W, Decraemer H, Nagga K, Minthon L, Londos E, Vanmechelen E, Holmberg B, Zetterberg H, Blennow K, Hansson O (2012) Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 69(11):1445–1452. doi: 10.1001/archneurol.2012.1654 CrossRefPubMedGoogle Scholar
  8. 8.
    Winge K, Jennum P, Lokkegaard A, Werdelin L (2010) Anal sphincter EMG in the diagnosis of parkinsonian syndromes. Acta Neurol Scand 121(3):198–203. doi: 10.1111/j.1600-0404.2009.01169.x CrossRefPubMedGoogle Scholar
  9. 9.
    Boeve BF, Lang AE, Litvan I (2003) Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 54(Suppl 5):S15–S19. doi: 10.1002/ana.10570 CrossRefPubMedGoogle Scholar
  10. 10.
    McKeith Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65(12):1863–1872. doi: 10.1212/01.wnl.0000187889.17253.b1 CrossRefPubMedGoogle Scholar
  11. 11.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9):670–676. doi: 10.1212/01.wnl.0000324625.00404.15 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ (2004) Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord 19(6):630–640. doi: 10.1002/mds.20083 CrossRefPubMedGoogle Scholar
  13. 13.
    Bloem BR, Grimbergen YA, Cramer M, Willemsen M, Zwinderman AH (2001) Prospective assessment of falls in Parkinson’s disease. J Neurol 248(11):950–958CrossRefPubMedGoogle Scholar
  14. 14.
    Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14(6):540–545PubMedGoogle Scholar
  15. 15.
    Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ (1989) The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res 28(2):193–213CrossRefPubMedGoogle Scholar
  16. 16.
    Fahn S, Elton R (1987) Unified Parkinson’s Disease Rating Scale. Recent developments in Parkinson’s disease. MacMillan Healthcare Information, Florham ParkGoogle Scholar
  17. 17.
    Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B, The Ataxia Neuropharmacology Committee of the World Federation of Neurology (1997) International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci 145(2):205–211CrossRefPubMedGoogle Scholar
  18. 18.
    Folstein MF, Robins LN, Helzer JE (1983) The mini-mental state examination. Arch Gen Psychiatry 40(7):812CrossRefPubMedGoogle Scholar
  19. 19.
    Meijer FJ, Aerts MB, Abdo WF, Prokop M, Borm GF, Esselink RA, Goraj B, Bloem BR (2012) Contribution of routine brain MRI to the differential diagnosis of parkinsonism: a 3-year prospective follow-up study. J Neurol 259(5):929–935. doi: 10.1007/s00415-011-6280-x PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, Wallin A, Ader H, Leys D, Pantoni L, Pasquier F, Erkinjuntti T, Scheltens P (2001) A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 32(6):1318–1322CrossRefPubMedGoogle Scholar
  21. 21.
    Yekhlef F, Ballan G, Macia F, Delmer O, Sourgen C, Tison F (2003) Routine MRI for the differential diagnosis of Parkinson’s disease, MSA, PSP, and CBD. J Neural Transm 110(2):151–169. doi: 10.1007/s00702-002-0785-5 CrossRefPubMedGoogle Scholar
  22. 22.
    Abdo WF, van de Warrenburg BP, Munneke M, van Geel WJ, Bloem BR, Kremer HP, Verbeek MM (2006) CSF analysis differentiates multiple-system atrophy from idiopathic late-onset cerebellar ataxia. Neurology 67(3):474–479. doi: 10.1212/01.wnl.0000227891.25592.8c CrossRefPubMedGoogle Scholar
  23. 23.
    Aerts MB, Esselink RA, Claassen JA, Abdo WF, Bloem BR, Verbeek MM (2011) CSF tau, Abeta42, and MHPG differentiate dementia with Lewy bodies from Alzheimer’s disease. J Alzheimers Dis 27(2):377–384. doi: 10.3233/JAD-2011-110482 PubMedGoogle Scholar
  24. 24.
    Brautigam C, Hyland K, Wevers R, Sharma R, Wagner L, Stock GJ, Heitmann F, Hoffmann GF (2002) Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic l-amino acid decarboxylase deficiency. Neuropediatrics 33(3):113–117. doi: 10.1055/s-2002-33673 CrossRefPubMedGoogle Scholar
  25. 25.
    van Geel WJ, Abdo WF, Melis R, Williams S, Bloem BR, Verbeek MM (2008) A more efficient enzyme-linked immunosorbent assay for measurement of alpha-synuclein in cerebrospinal fluid. J Neurosci Methods 168(1):182–185. doi: 10.1016/j.jneumeth.2007.09.021 CrossRefPubMedGoogle Scholar
  26. 26.
    van Royen E, Verhoeff NF, Speelman JD, Wolters EC, Kuiper MA, Janssen AG (1993) Multiple system atrophy and progressive supranuclear palsy. Diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM single photon emission computed tomography. Arch Neurol 50(5):513–516CrossRefPubMedGoogle Scholar
  27. 27.
    Podnar S, Fowler CJ (2004) Sphincter electromyography in diagnosis of multiple system atrophy: technical issues. Muscle Nerve 29(1):151–156. doi: 10.1002/mus.10478 CrossRefPubMedGoogle Scholar
  28. 28.
    Bloem BR, Bhatia KP (2004) Gait and balance in basal ganglia disorders. Clinical disorders of balance, posture and gait, Arnold, LondonGoogle Scholar
  29. 29.
    Bloem BR, Beckley DJ, van Hilten BJ, Roos RA (1998) Clinimetrics of postural instability in Parkinson’s disease. J Neurol 245(10):669–673CrossRefPubMedGoogle Scholar
  30. 30.
    Jacobs JV, Horak FB, Tran VK, Nutt JG (2006) Multiple balance tests improve the assessment of postural stability in subjects with Parkinson’s disease. J Neurol Neurosurg Psychiatry 77(3):322–326. doi: 10.1136/jnnp.2005.068742 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Bohnen NI, Studenski SA, Constantine GM, Moore RY (2008) Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study. Eur J Neurol 15(7):685–691. doi: 10.1111/j.1468-1331.2008.02148.x CrossRefPubMedGoogle Scholar
  32. 32.
    Tang CC, Poston KL, Eckert T, Feigin A, Frucht S, Gudesblatt M, Dhawan V, Lesser M, Vonsattel JP, Fahn S, Eidelberg D (2010) Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 9(2):149–158. doi: 10.1016/S1474-4422(10)70002-8 CrossRefPubMedGoogle Scholar
  33. 33.
    Schrag A, Good CD, Miszkiel K, Morris HR, Mathias CJ, Lees AJ, Quinn NP (2000) Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 54(3):697–702CrossRefPubMedGoogle Scholar
  34. 34.
    Yekhlef F, Ballan G, Macia F, Delmer O, Sourgen C, Tison F (2003) Routine MRI for the differential diagnosis of Parkinson’s disease, MSA, PSP, and CBD. J Neural Transm 110(2):151–169. doi: 10.1007/s00702-002-0785-5 CrossRefPubMedGoogle Scholar
  35. 35.
    Savoiardo M (2003) Differential diagnosis of Parkinson’s disease and atypical parkinsonian disorders by magnetic resonance imaging. Neurol Sci 24(Suppl 1):S35–S37. doi: 10.1007/s100720300036 CrossRefPubMedGoogle Scholar
  36. 36.
    Berardelli A, Wenning GK, Antonini A, Berg D, Bloem BR, Bonifati V, Brooks D, Burn DJ, Colosimo C, Fanciulli A, Ferreira J, Gasser T, Grandas F, Kanovsky P, Kostic V, Kulisevsky J, Oertel W, Poewe W, Reese JP, Relja M, Ruzicka E, Schrag A, Seppi K, Taba P, Vidailhet M (2013) EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 20(1):16–34. doi: 10.1111/ene.12022 CrossRefPubMedGoogle Scholar
  37. 37.
    de Lau LM, Giesbergen PC, de Rijk MC, Hofman A, Koudstaal PJ, Breteler MM (2004) Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology 63(7):1240–1244CrossRefPubMedGoogle Scholar
  38. 38.
    Seppi K, Schocke MF (2005) An update on conventional and advanced magnetic resonance imaging techniques in the differential diagnosis of neurodegenerative parkinsonism. Curr Opin Neurol 18(4):370–375CrossRefPubMedGoogle Scholar
  39. 39.
    van de Loo S, Walter U, Behnke S, Hagenah J, Lorenz M, Sitzer M, Hilker R, Berg D (2010) Reproducibility and diagnostic accuracy of substantia nigra sonography for the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 81(10):1087–1092. doi: 10.1136/jnnp.2009.196352 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • M. B. Aerts
    • 1
  • R. A. J. Esselink
    • 1
  • W. F. Abdo
    • 1
    • 2
  • F. J. A. Meijer
    • 3
  • G. Drost
    • 1
  • N. Norgren
    • 4
  • M. J. R. Janssen
    • 5
  • G. F. Borm
    • 6
  • B. R. Bloem
    • 1
    Email author
  • M. M. Verbeek
    • 1
  1. 1.Department of Neurology, Parkinson Center Nijmegen (ParC), Donders Institute for Brain Cognition and BehaviourRadboud University Medical CenterNijmegenThe Netherlands
  2. 2.Department of Intensive Care MedicineRadboud University Medical CenterNijmegenThe Netherlands
  3. 3.Department of RadiologyRadboud University Medical CenterNijmegenThe Netherlands
  4. 4.Uman Diagnostics ABUmeaSweden
  5. 5.Department of Nuclear MedicineRadboud University Medical CenterNijmegenThe Netherlands
  6. 6.Department of Epidemiology, Biostatistics and HTARadboud University Medical CenterNijmegenThe Netherlands

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