Skip to main content

Optimizing the selection of Parkinson’s disease patients for neuromodulation using the levodopa challenge test



In Parkinson’s disease (PD), early stages are associated with a good long-duration response and as the disease advances, the short-duration response predominates. The transition between the long-duration and short-duration responses may be an important and measurable intermediate stage. A critical criterion in determining the candidature for neuromodulation is a beneficial response to an ‘off–on’ levodopa challenge test. This test is usually reserved for those that have already developed marked short-duration response and are candidates for deep brain stimulation (DBS) surgery. However, identifying those that are in transition may allow DBS to be offered earlier.


The objective of the study was to determine if the transition from a long-duration to a short-duration response can be assessed on a levodopa challenge test.


An ‘off–on” levodopa challenge test was done in sixty-five PD patients divided into four groups based on the disease duration.


OFF motor scores increased in all groups [Mean ± STD; 22.94 ± 8.52, 31.53 ± 9.87, 34.05 ± 9.50, and 33.92 ± 10.15 in groups 1–4, respectively] while a significant response to medication was maintained on ‘off–on’ testing. The mean levodopa equivalency dose in groups 1 and 2 was significantly less than in groups 3 and 4. This transition occurred between years 7 and 9 of disease duration.


Performing a regular levodopa challenge test, when levodopa dose increases substantially, should be considered to determine the ideal time for DBS in patients with Parkinson’s disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Availability of data and material

The data are available on request submitted to the institutional ethics committee.


  1. Salat D, Tolosa E (2013) Levodopa in the treatment of Parkinson’s disease: current status and new developments. J Park Dis 3(3):255–269.

    CAS  Article  Google Scholar 

  2. Poewe W (2009) Clinical measures of progression in Parkinson’s disease. Mov Disord Off J Mov Disord Soc 24(Suppl 2):S671-676.

    Article  Google Scholar 

  3. Anderson E, Nutt J (2011) The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord 17(8):587–592.

    Article  PubMed  Google Scholar 

  4. Nutt JG, Carter JH, Woodward WR (1995) Long-duration response to levodopa. Neurology 45(8):1613–1616.

    CAS  Article  PubMed  Google Scholar 

  5. Zappia M et al (1999) Loss of long-duration response to levodopa over time in PD: implications for wearing-off. Neurology 52(4):763–767.

    CAS  Article  PubMed  Google Scholar 

  6. Saranza G, Lang AE (2020) Levodopa challenge test: indications, protocol, and guide. J Neurol.

    Article  PubMed  Google Scholar 

  7. Defer GL, Widner H, Marié RM, Rémy P, Levivier M (1999) Core assessment program for surgical interventional therapies in Parkinson’s disease (CAPSIT-PD). Mov Disord Off J Mov Disord Soc 14(4):572–584.;2-C

    CAS  Article  Google Scholar 

  8. Pollak P (2013) Deep brain stimulation for Parkinson’s disease - patient selection. Handb Clin Neurol 116:97–105.

    Article  PubMed  Google Scholar 

  9. Schuepbach WMM et al (2013) Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med 368(7):610–622.

    CAS  Article  PubMed  Google Scholar 

  10. Calabresi P, Picconi B, Tozzi A, Ghiglieri V, Di Filippo M (2014) Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci 17(8):1022–1030.

    CAS  Article  PubMed  Google Scholar 

  11. Mura A, Jackson D, Manley MS, Young SJ, Groves PM (1995) Aromatic L-amino acid decarboxylase immunoreactive cells in the rat striatum: a possible site for the conversion of exogenous L-DOPA to dopamine. Brain Res 704(1):51–60.

    CAS  Article  PubMed  Google Scholar 

  12. Tanaka H, Kannari K, Maeda T, Tomiyama M, Suda T, Matsunaga M (1999) Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. NeuroReport 10(3):631–634.

    CAS  Article  PubMed  Google Scholar 

  13. Bordia T, Perez XA, Heiss J, Zhang D, Quik M (2016) Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias. Neurobiol Dis 91:47–58.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Stocchi P, Jenner JA (2010) Obeso, “When do levodopa motor fluctuations first appear in Parkinson’s disease?” Eur Neurol 63(5):257–266.

    CAS  Article  PubMed  Google Scholar 

  15. McFarland NR (2016) Diagnostic approach to atypical parkinsonian syndromes. Continuum (Minneap Minn). 22(4):1117–1142.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhao YJ, Wee HL, Chan YH, Seah SH, Au WL, Lau PN, Pica EC, Li SC, Luo N, Tan LC (2010) Progression of Parkinson’s disease as evaluated by Hoehn and Yahr stage transition times. Mov Disord 25(6):710–716.

    Article  PubMed  Google Scholar 

  17. 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(15):2649–2653.

    Article  PubMed  Google Scholar 

  18. Clissold BG, McColl CD, Reardon KR, Shiff M, Kempster PA (2006) Longitudinal study of the motor response to levodopa in Parkinson’s disease. Mov Disord Off J Mov Disord Soc 21(12):2116–2121.

    Article  Google Scholar 

  19. Artusi CA, Lopiano L, Morgante F (2020) Deep brain stimulation selection criteria for Parkinson’s Disease: Time to Go beyond CAPSIT-PD. J Med Clin.

    Article  Google Scholar 

  20. Morishita T et al (2011) DBS candidates that fall short on a levodopa challenge test: alternative and important indications. Neurologist 17(5):263–268.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nutt JG, Carter JH, Lea ES, Sexton GJ (2002) Evolution of the response to levodopa during the first 4 years of therapy. Ann Neurol 51(6):686–693.

    CAS  Article  PubMed  Google Scholar 

  22. Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, Halliday GM, Bartus RT (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136(Pt 8):2419–2431.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Volkmann J (2004) Deep brain stimulation for the treatment of Parkinson’s disease. J Clin Neurophysiol Off Publ Am Electroencephalogr Soc 21(1):6–17.

    Article  Google Scholar 

  24. Wider C et al (2006) Long-duration response to levodopa in patients with advanced Parkinson disease treated with subthalamic deep brain stimulation. Arch Neurol 63(7):951–955.

    Article  PubMed  Google Scholar 

  25. Moro E, Esselink RJA, Benabid AL, Pollak P (2002) Response to levodopa in parkinsonian patients with bilateral subthalamic nucleus stimulation. Brain J Neurol 125(Pt 11):2408–2417.

    Article  Google Scholar 

  26. Brandão P, Grippe TC, Modesto LC, Ferreira AGF, Silva FMD, Pereira FF, Lobo ME, Allam N, Freitas TDS, Munhoz RP (2018) Decisions about deep brain stimulation therapy in Parkinson’s disease. Arq Neuropsiquiatr 76(6):411–420. (PMID: 29972424)

    Article  PubMed  Google Scholar 

Download references


No funding was received for conducting this study.

Author information

Authors and Affiliations



All authors contributed to study conception and design. Material preparation and data collection were carried out by MP. The first draft of the manuscript was prepared by DK, GG. The writing – review and editing was done by DK, GG and MJ. The study was carried out under the supervision of MJ.

Corresponding author

Correspondence to Mandar Jog.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics statement

The study was approved by the institutional ethics committee and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments (REB #107253).

Consent to participate

An informed consent was obtained from all patients included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kulshreshtha, D., Pieterman, M., Gilmore, G. et al. Optimizing the selection of Parkinson’s disease patients for neuromodulation using the levodopa challenge test. J Neurol 269, 846–852 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Parkinson’s disease
  • Levodopa challenge test
  • Deep brain stimulation
  • Short-duration response
  • Long-duration response