Skip to main content
SpringerLink
Log in

Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson’s disease

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

The differential diagnosis between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson’s disease (PD) may be challenging at disease onset. Levodopa responsiveness helps distinguish the two groups, but studies evaluating this issue using objective standardized tests are scanty. We retrospectively examined the extent of levodopa response by an objective kinetic-dynamic test in a series of patients prospectively followed up for a parkinsonian syndrome and eventually diagnosed as MSA-P or PD. Sixteen MSA-P and 31 PD patients under chronic levodopa therapy received a first morning fasting dose of levodopa/benserazide (100/25 mg) or levodopa/carbidopa (125/12.5 or 100/25 mg) and underwent simultaneous serial assessments of plasma levodopa concentration and alternate finger tapping frequency up to 3 h post dosing. The main levodopa pharmacodynamic variables were the maximum percentage increase in tapping frequency over baseline values (ΔTapmax %) and the area under the tapping effect–time curve (AUCTap). Levodopa pharmacokinetics did not show significant differences between MSA-P and PD, whereas both the magnitude and overall extent of levodopa tapping effect were markedly reduced in the MSA-P group (p < 0.001). The combined use of specific cut-off values for both the main pharmacodynamic variables, ΔTapmax % <20 % and AUCTap <1900 [(tapping/min)·min], correctly discriminated 15 out of 16 MSA-P patients from PD patients. A combined estimation of these pharmacodynamic variables after a subacute low levodopa dose may be a simple and practical clinical tool to aid the differential diagnosis between MSA-P and PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Dürr 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 71:670–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:249–263

    Article  PubMed  Google Scholar 

  3. Baschieri F, Calandra-Buonaura G, Doria A, Mastrolilli F, Palareti A, Barletta G, Solieri L, Guaraldi P, Martinelli P, Cortelli P (2015) Cardiovascular autonomic testing performed with a new integrated instrumental approach is useful in differentiating MSA-P from PD at an early stage. Parkinsonism Relat Disord 21:477–482

    Article  PubMed  Google Scholar 

  4. Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56:33–39

    Article  CAS  PubMed  Google Scholar 

  6. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP (1997) Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 12:133–147

    Article  CAS  PubMed  Google Scholar 

  7. Gilman S, May SJ, Shults CW, Tanner CM, Kukull W, Lee VM, Masliah E, Low P, Sandroni P, Trojanowski JQ, Ozelius L, Foroud T (2005) North American Multiple System Atrophy Study Group. J Neural Transm 112:1687–1694

    Article  CAS  PubMed  Google Scholar 

  8. Köllensperger M, Geser F, Ndayisaba JP, Boesch S, Seppi K, Ostergaard K, Dupont E, Cardozo A, Tolosa E, Abele M, Klockgether T, Yekhlef F, Tison F, Daniels C, Deuschl G, Coelho M, Sampaio C, Bozi M, Quinn N, Schrag A, Mathias CJ, Fowler C, Nilsson CF, Widner H, Schimke N, Oertel W, Del Sorbo F, Albanese A, Pellecchia MT, Barone P, Djaldetti R, Colosimo C, Meco G, Gonzalez-Mandly A, Berciano J, Gurevich T, Giladi N, Galitzky M, Rascol O, Kamm C, Gasser T, Siebert U, Poewe W, Wenning GK, EMSA-SG (2010) Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov Disord 25:2604–2612

    Article  PubMed  Google Scholar 

  9. Wenning GK, Geser F, Krismer F, Seppi K, Duerr S, Boesch S, Köllensperger M, Goebel G, Pfeiffer KP, Barone P, Pellecchia MT, Quinn NP, Koukouni V, Fowler CJ, Schrag A, Mathias CJ, Giladi N, Gurevich T, Dupont E, Ostergaard K, Nilsson CF, Widner H, Oertel W, Eggert KM, Albanese A, del Sorbo F, Tolosa E, Cardozo A, Deuschl G, Hellriegel H, Klockgether T, Dodel R, Sampaio C, Coelho M, Djaldetti R, Melamed E, Gasser T, Kamm C, Meco G, Colosimo C, Rascol O, Meissner WG, Tison F, Poewe W, European Multiple System Atrophy Study Group (2013) The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 12:264–274

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hughes AJ, Colosimo C, Kleedorfer B, Daniel SE, Lees AJ (1992) The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry 55:1009–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Parati EA, Fetoni V, Geminiani GC, Soliveri P, Giovannini P, Testa D, Genitrini S, Caraceni T, Girotti F (1993) Response to L-DOPA in multiple system atrophy. Clin Neuropharmacol 16:139–144

    Article  CAS  PubMed  Google Scholar 

  12. Contin M, Riva R, Martinelli P, Albani F, Avoni P, Baruzzi A (2001) Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach. Ther Drug Monit 23:621–629

    Article  CAS  PubMed  Google Scholar 

  13. Contin M, Riva R, Martinelli P, Cortelli P, Albani F, Baruzzi A (1998) A levodopa kinetic-dynamic study of the rate of progression in Parkinson’s disease. Neurology 51:1075–1080

    Article  CAS  PubMed  Google Scholar 

  14. Contin M, Martinelli P, Riva R, Dondi M, Fanti S, Pettinato C, Scaglione C, Albani F, Baruzzi A (2003) Assessing dopaminergic function in Parkinson’s disease: levodopa kinetic-dynamic modeling and SPECT. J Neurol 250:1475–1481

    Article  CAS  PubMed  Google Scholar 

  15. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow CW, Tanner C, Marek K (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351:2498–2508

    Article  CAS  PubMed  Google Scholar 

  16. Baruzzi A, Contin M, Albani F, Riva R (1986) Simple and rapid micromethod for the determination of levodopa and 3-O-methyldopa in human plasma by high-performance liquid chromatography with coulometric detection. J Chromatogr 375:165–169

    Article  CAS  Google Scholar 

  17. Hagell P, Widner H (1999) Clinical rating of dyskinesias in Parkinson’s disease: use and reliability of a new rating scale. Mov Disord 14:448–455

    Article  CAS  PubMed  Google Scholar 

  18. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM, van Dijk JG (2011) Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 21:69–72

    Article  PubMed  Google Scholar 

  19. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE (2010) Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 25:2649–2653

    Article  PubMed  Google Scholar 

  20. Nutt JG, Woodward WR, Carter JH, Gancher ST (1992) Effect of long-term therapy on the pharmacodynamics of levodopa. Relation to on-off phenomenon. Arch Neurol 49:1123–1130

    Article  CAS  PubMed  Google Scholar 

  21. Colosimo C, Merello M, Hughes AJ, Sieradzan K, Lees AJ (1996) Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson’s disease: implications for the pathogenesis of the on-off phenomenon. J Neurol Neurosurg Psychiatry 60:634–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Harder S, Baas H (1998) Concentration-response relationship of levodopa in patients at different stages of Parkinson’s disease. Clin Pharmacol Ther 64:183–191

    Article  CAS  PubMed  Google Scholar 

  23. Fearnley JM, Lees AJ (1990) Striatonigral degeneration. A clinicopathological study. Brain 113:1823–1842

    Article  PubMed  Google Scholar 

  24. Ramaker C, Marinus J, Stiggelbout AM, van Hilten BJ (2002) Systematic evaluation of rating scales for impairment and disability in Parkinson’s disease. Mov Disord 17:867–876

    Article  PubMed  Google Scholar 

  25. Robertson DR, Renwick AG, Macklin B, Jones S, Waller DG, George CF, Fleming JS (1992) The influence of levodopa on gastric emptying in healthy eldery volunteers. Eur J Clin Pharmacol 42:409–412

    CAS  PubMed  Google Scholar 

  26. Defer GL, Widner H, Marie RM, Remy P, Levivier M (1999) Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord 14:572–584

    Article  CAS  PubMed  Google Scholar 

  27. Michely J, Volz LJ, Barbe MT, Hoffstaedter F, Viswanathan S, Timmermann L, Eickhoff SB, Fink GR, Grefkes C (2005) Dopaminergic modulation of motor network dynamics in Parkinson’s disease. Brain 138:664–678

    Article  Google Scholar 

  28. Agostino R, Berardelli A, Currà A, Accornero N, Manfredi M (1998) Clinical impairment of sequential finger movements in Parkinson’s disease. Mov Disord 13:418–421

    Article  CAS  PubMed  Google Scholar 

  29. Pal PK, Lee CS, Samii A, Schulzer M, Stoessl AJ, Mak EK, Wudel J, Dobko T, Tsui JK (2001) Alternating two finger tapping with contralateral activation is an objective measure of clinical severity in Parkinson’s disease and correlates with PET. Parkinsonism Relat Disord 7:305–309

    Article  PubMed  Google Scholar 

  30. Potter-Nerger M, Wenzelburger R, Deuschl G, Volkmann J (2009) Impact of subthalamic stimulation and medication on proximal and distal bradykinesia in Parkinson’s disease. Eur Neurol 62:114–119

    Article  CAS  PubMed  Google Scholar 

  31. Homann CN, Suppan K, Wenzel K, Giovannoni G, Ivanic G, Horner S, Ott E, Hartung HP (2000) The Bradykinesia Akinesia Incoordination Test (BRAIN TEST), an objective and user-friendly means to evaluate patients with parkinsonism. Mov Disord 15:641–647

    Article  CAS  PubMed  Google Scholar 

  32. Taylor Tavares AL, Jefferis GS, Koop M, Hill BC, Hastie T, Heit G, Bronte-Stewart HM (2005) Quantitative measurements of alternating finger tapping in Parkinson’s disease correlate with UPDRS motor disability and reveal the improvement in fine motor control from medication and deep brain stimulation. Mov Disord 20:1286–1298

    Article  PubMed  Google Scholar 

  33. Sambati L, Calandra-Buonaura G, Doria A, Cortelli P (2015) Diagnosis and management of autonomic failure in neurodegenerative disorders. Eur Neurol 73:126–133

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The skilful nursing and technical assistance of Anita Calisti and Carmina Candela are gratefully acknowledged. Anne Prudence Collins edited the English text. No specific funding was received to perform this study.

Author information

Authors and Affiliations

  1. IRCCS, Institute of Neurological Sciences of Bologna, c/o Padiglione G, Ospedale Bellaria, Via Altura 3, 40139, Bologna, Italy

    Giovanna Calandra-Buonaura, Giovanna Lopane, Sabina Capellari, Pietro Cortelli & Manuela Contin

  2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy

    Giovanna Calandra-Buonaura, Andrea Doria, Sabina Capellari, Paolo Martinelli, Pietro Cortelli & Manuela Contin

  3. Neurology Outpatient Clinic, Department of Primary Care, Modena Local Health Authority, Modena, Italy

    Pietro Guaraldi

Authors
  1. Giovanna Calandra-Buonaura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Doria
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giovanna Lopane
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pietro Guaraldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabina Capellari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paolo Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pietro Cortelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuela Contin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pietro Cortelli.

Ethics declarations

Conflicts of interest

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

Ethical standards

The study was approved by the DIBINEM—University of Bologna institutional review board and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Patients had given their written informed consent to personal data processing for research purposes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calandra-Buonaura, G., Doria, A., Lopane, G. et al. Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson’s disease. J Neurol 263, 250–256 (2016). https://doi.org/10.1007/s00415-015-7961-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-015-7961-7

Keywords

Search

Navigation