Skip to main content

Cardiovascular autonomic neuropathy and falls in Parkinson disease: a prospective cohort study

Abstract

Background

Falls represent one of the main complications of Parkinson’s disease (PD), significantly lowering quality of life. Cardiovascular autonomic neuropathy (cAN) is one of the key contributing factors to PD-associated falls. However, a direct quantification of its impact on the risk of falling in PD is still lacking. In this 12-month prospective study, we sought to evaluate the association between cAN and falls.

Methods

Fifty consecutive patients were evaluated with a standardized battery of autonomic testing, Unified Parkinson’s Disease Rating Scale, push and release (P&R) test, timed up and go test, freezing of gait (FOG) questionnaire, Montreal cognitive assessment (MoCA). Dyskinesia severity and presence of REM sleep behavioral disorder (RBD) were additionally considered. Patients were followed-up for 12 months.

Results

We observed a 38% prevalence of cAN. At baseline, 36% of patients reported at least one fall in the previous 6 months. This figure increased to 56% over the follow-up. After adjusting for age, disease duration, axial symptoms, MoCA and dopaminergic treatment, cAN was significantly associated with a 15-fold (OR 15.194) higher probability of falls; orthostatic hypotension (OH), the most common expression of cAN, with a 10-fold probability (OR 10.702). In addition P&R test (OR 14.021), RBD (OR 5.470) and FOG (OR 1.450) were independently associated with greater probability of falls.

Conclusions

cAN, including but not limited to OH, is a strong independent predictor of falls in PD. Future research endeavors clarifying to what extent pharmacological and non-pharmacological treatments targeting autonomic dysfunctions might reduce the risk of falls are warranted.

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

Fig. 1
Fig. 2

References

  1. 1.

    Fasano A, Canning CG, Hausdorff JM, Lord S, Rochester L (2017) Falls in Parkinson’s disease: a complex and evolving picture. Mov Disord 32:1524–1536

    Article  Google Scholar 

  2. 2.

    Thurman DJ, Stevens JA, Rao JK, Quality Standards Subcommittee of the American Academy of N (2008) Practice parameter: assessing patients in a neurology practice for risk of falls (an evidence-based review): report of the quality standards subcommittee of the american academy of neurology. Neurology 70:473–479

    Article  PubMed  Google Scholar 

  3. 3.

    Bloem BR, Bhatia KP (2004) Basal ganglia disorders. In: Bronstein AM, Woollacott MH, Nutt JG (eds) Clinical disorders of balance, posture and gait, 2nd edn. Arnold, London, pp 173–206

    Google Scholar 

  4. 4.

    Espay AJ, LeWitt PA, Hauser RA, Merola A, Masellis M, Lang AE (2016) Neurogenic orthostatic hypotension and supine hypertension in Parkinson’s disease and related synucleinopathies: prioritisation of treatment targets. Lancet Neurol 15:954–966

    Article  PubMed  Google Scholar 

  5. 5.

    van der Marck MA, Klok MP, Okun MS, Giladi N, Munneke M, Bloem BR, NPF Falls Task Force (2014) Consensus-based clinical practice recommendations for the examination and management of falls in patients with Parkinson’s disease. Parkinsonism Relat Disord 20:360–369

    Article  PubMed  Google Scholar 

  6. 6.

    Pickering RM, Grimbergen YA, Rigney U et al (2007) A meta-analysis of six prospective studies of falling in Parkinson’s disease. Mov Disord 22:1892–1900

    Article  PubMed  Google Scholar 

  7. 7.

    Chou KL, Elm JJ, Wielinski CL et al (2017) Factors associated with falling in early, treated Parkinson’s disease: The NET-PD LS1 cohort. J Neurol Sci 377:137–143

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Gibb WRG, 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 

  9. 9.

    Dineen J, Freeman R (2015) Autonomic neuropathy. Semin Neurol 35:458–468

    Article  PubMed  Google Scholar 

  10. 10.

    Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease (2003) The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 18:738–750

    Article  Google Scholar 

  11. 11.

    Levy G, Louis ED, Cote L et al (2005) Contribution of aging to the severity of different motor signs in Parkinson disease. Arch Neurol 62:467–472

    Article  PubMed  Google Scholar 

  12. 12.

    Valkovic P, Brozova H, Botzel K, Ruzicka E, Benetin J (2008) Push-and-release test predicts Parkinson fallers and nonfallers better than the pull test: comparison in OFF and ON medication states. Mov Disord 23:1453–1457

    Article  PubMed  Google Scholar 

  13. 13.

    Viccaro LJ, Perera S, Studenski SA (2011) Is timed up and go better than gait speed in predicting health, function, and falls in older adults? J Am Geriatr Soc 59:887–892

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Giladi N, Shabtai H, Simon ES, Biran S, Tal J, Korczyn AD (2000) Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat Disord 6:165–170

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Nasreddine ZS, Phillips NA, Bédirian V et al (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:695–699

    Article  PubMed  Google Scholar 

  16. 16.

    Postuma RB, Arnulf I, Hogl B et al (2012) A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. Mov Disord 27:913–916

    Article  PubMed  PubMed Central  Google Scholar 

  17. 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 25:2649–2653

    Article  Google Scholar 

  18. 18.

    Low PA, Tomalia VA, Park KJ (2013) Autonomic function tests: some clinical applications. J Clin Neurol 9:1–8

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W, Tassinari M (2006) EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neurol 13:930–936

    Article  CAS  Google Scholar 

  20. 20.

    Fleiss JL, Tytun A, Ury HK (1980) A simple approximation for calculating sample sizes for comparing independent proportions. Biometrics 36:343–346

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    De Luka SR, Svetel M, Pekmezović T, Milovanović B, Kostić VS (2014) When do the symptoms of autonomic nervous system malfunction appear in patients with Parkinson’s disease? Vojnosanit Pregl 71:346–351

    Article  PubMed  Google Scholar 

  22. 22.

    Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB (2015) New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes. JAMA Neurol 72:863–873

    Article  PubMed  Google Scholar 

  23. 23.

    Goldstein DS, Holmes C, Sharabi Y, Wu T (2015) Survival in synucleinopathies: a prospective cohort study. Neurology 85:1554–1561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Merola A, Romagnolo A, Comi C et al (2017) Prevalence and burden of dysautonomia in advanced Parkinson’s disease. Mov Disord 32:796–797

    Article  PubMed  Google Scholar 

  25. 25.

    Merola A, Romagnolo A, Rosso M et al (2016) Orthostatic hypotension in Parkinson’s disease: does it matter if asymptomatic? Parkinsonism Relat Disord 33:65–71

    Article  PubMed  Google Scholar 

  26. 26.

    Merola A, Sawyer RP, Artusi CA et al (2018) Orthostatic hypotension in Parkinson disease: impact on health care utilization. Parkinsonism Relat Disord 47:45–49

    Article  PubMed  Google Scholar 

  27. 27.

    Balaban CD, Porter JD (1998) Neuroanatomic substrates for vestibuloautonomicinteractions. J Vestib Res 8:7–16

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Martignoni E, Tassorelli C, Nappi G (2006) Cardiovascular dysautonomia as a cause of falls in Parkinson’s disease. Parkinsonism Relat Disord 12:195–204

    Article  PubMed  Google Scholar 

  29. 29.

    Jacobs JV, Earhart GM, McNeely ME (2016) Can postural instability tests improve the prediction of future falls in people with Parkinson’s disease beyond knowing existing fall history? J Neurol 263:133–139

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Romenets SR, Gagnon JF, Latreille V, Panniset M, Chouinard S, Montplaisir J, Postuma RB (2012) Rapid eye movement sleep behavior disorder and subtypes of Parkinson’s disease. Mov Disord 27:996–1003

    Article  PubMed  Google Scholar 

  31. 31.

    Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C (2011) Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology 77:1048–1054

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Suzuki K, Okuma Y, Uchiyama T et al (2017) Impact of sleep-related symptoms on clinical motor subtypes and disability in Parkinson’s disease: A multicentre cross-sectional study. J Neurol Neurosurg Psychiatry 88:953–959

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Lavault S, Leu-Semenescu S, Tezenas Du Montcel S, Cochen De Cock V, Vidailhet M, Arnulf I (2010) Does clinical rapid eye movement behavior disorder predict worse outcomes in Parkinson’s disease? J Neurol 257:1154–1159

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Kim JS, Oh YS, Lee KS, Kim YI, Yang DW, Goldstein DS (2012) Association of cognitive dysfunction with neurocirculatory abnormalities in early Parkinson disease. Neurology 79:1323–1331

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kotagal V, Albin RL, Muller ML, Koeppe RA, Chervin RD, Frey KA, Bohnen NI (2013) Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann Neurol 71:560–568

    Article  CAS  Google Scholar 

  36. 36.

    Bohnen NI, Muller ML, Koeppe RA, Studenski SA, Kilbourn MA, Frey KA, Albin RL (2009) History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 73:1670–1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Muller ML, Bohnen NI, Kotagal V, Scott PJ, Koeppe RA, Frey KA, Albin RL (2015) Clinical markers for identifying cholinergic deficits in Parkinson’s disease. Mov Disord 30:269–273

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Palma JA, Gomez-Esteban JC, Norcliffe-Kaufmann L, Martinez J, Tijero B, Berganzo K, Kaufmann H (2015) Orthostatic hypotension in Parkinson disease: how much you fall or how low you go? Mov Disord 30:639–645

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Nothing to declare.

Author information

Affiliations

Authors

Contributions

AR: conception and design of the study; acquisition, analysis and interpretation of data; writing of the first draft and review and critique of the manuscript. MZ: conception and design of the study; analysis and interpretation of data; writing of the first draft and review and critique of the manuscript. AM: design of the study; analysis and interpretation of data; review and critique of the manuscript. DC: design of the study; analysis and interpretation of data; review and critique of the manuscript. MS: design of the study; acquisition and interpretation of data; review and critique of the manuscript. EM: design of the study; acquisition and interpretation of data; review and critique of the manuscript. ACA: design of the study; acquisition and interpretation of data; review and critique of the manuscript. FV: design of the study; acquisition and interpretation of data; review and critique of the manuscript. SM: design of the study; analysis and interpretation of data; review and critique of the manuscript. LL: conception and design of the study; analysis and interpretation of data; review and critique of the manuscript. All the co-authors listed above gave their final approval of this manuscript version.

Corresponding author

Correspondence to Alberto Romagnolo.

Ethics declarations

Conflicts of interest

Dr Romagnolo has received grant support and speaker honoraria from AbbVie, speaker honoraria from Chiesi Farmaceutici and travel grants from Medtronic, Lusofarmaco and UCB Pharma. Dr Zibetti has received speaker’s honoraria from Medtronic, Chiesi Farmaceutici, UCB Pharma, and AbbVie. Dr Merola is supported by NIH (KL2 TR001426) and has received speaker honoraria from CSL Behring, Abbvie, and Cynapsus Therapeutics. He has received grant support from Lundbeck. Dr Canova reports no disclosures. Dr Sarchioto reports no disclosures Dr Montanaro reports no disclosures. Dr Artusi reports no disclosures. Dr Vallelonga reports no disclosures. Dr Maule reports no disclosures. Dr Lopiano has received honoraria for lecturing and travel grants from Medtronic, UCB Pharma and AbbVie.

Data access and responsibility statement

A. Romagnolo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Ethical standard

The authors declare that they acted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The local institutional review board (Comitato Etico Interaziendale Città della Salute e della Scienza di Torino; Protocol n° 0050175/CEI-715) approved the study and all participants provided written informed consent.

Additional information

Dr Romagnolo and Dr Zibetti contributed equally to this manuscript

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Romagnolo, A., Zibetti, M., Merola, A. et al. Cardiovascular autonomic neuropathy and falls in Parkinson disease: a prospective cohort study. J Neurol 266, 85–91 (2019). https://doi.org/10.1007/s00415-018-9104-4

Download citation

Keywords

  • Parkinson disease
  • Autonomic neuropathy
  • Falls
  • Orthostatic hypotension
  • RBD