Journal of Neurology

, Volume 265, Issue 4, pp 933–941 | Cite as

Heterogeneous pattern of autonomic dysfunction in Parkinson’s disease

  • Laurène Leclair-VisonneauEmail author
  • Laurent Magy
  • Christelle Volteau
  • Thomas Clairembault
  • Séverine Le Dily
  • Cécile Préterre
  • Arnaud Peyre
  • Philippe Damier
  • Michel Neunlist
  • Yann Péréon
  • Pascal Derkinderen
Original Communication


Dysautonomic symptoms are frequent non-motor complaints in patients with Parkinson’s disease. Numerous neuropathological studies have shown that Lewy bodies and neurites, the pathological hallmarks of Parkinson’s disease, are widely distributed throughout the peripheral autonomic nervous systems and across end organs. However, few investigations integrally explored the symptoms and physiology of dysautonomia in Parkinson’s disease. We, therefore, performed a comprehensive evaluation of the autonomic function in a prospective group of 45 patients with idiopathic Parkinson’s disease. Autonomic components (pupillomotor, tear, salivary, cardiovascular, digestive, urinary, sexual, sudomotor functions and skin sensitivity) were evaluated using questionnaires and functional tests. Skin biopsy was performed for intraepidermal nerve fibre density quantification. In addition, all patients underwent polysomnography and a complete neuropsychological and neurological assessment. The analysis association of autonomic components showed that dysautonomic signs and symptoms were heterogeneously distributed among patients. Skin denervation as assessed by intraepidermal nerve fibre density quantification was only associated with quantitative thermal sensory testing (OR = 12.0, p = 0.02), constipation (OR = 5.5, p = 0.01) and ocular dryness symptoms (OR = 8.29, p = 0.04). Cognitive alteration was associated with cardiovascular symptoms (OR = 4.33, p = 0.03) and dysfunction (OR = 5.83, p = 0.02) as well as with constipation (OR = 5.38, p = 0.02). Axial motor impairment and rapid eye movement (REM) sleep behaviour disorder were not related to any of the autonomic complaint or dysfunction. Our results show that autonomic functions are affected in a heterogeneous pattern in Parkinson’s disease, thereby suggesting that the progression of autonomic dysfunction follows an erratic rather than a stepwise progression.


Dysautonomia Electrophysiology Intraepidermal nerve fibre density Parkinson’s disease Cognitive alteration 



Autonomic nervous system


Enteric nervous system


Intraepidermal nerve fibre


Mattis dementia rating scale


Mini-mental state examination


Montreal cognitive assessment


Nerve conduction velocity


Non-motor symptoms questionnaire


Parkinson’s disease


Quantitative thermal sensory testing


Rapid eye movement sleep behaviour disorder


Rapid eye movement


SCales for Outcomes in PArkinson’s disease-autonomic symptoms


Sympathetic skin response


Unified Parkinson’s disease rating scale part III



Laurence Richard, Fanny Maquin, Monique Marguerite, Aurélie Grateau, Marion Rigot, Monica Roy, Aurélie Delhumeau and Alexandra Gosseaume for technical assistance, collecting and monitoring data. Tiphaine Rouaud, Violaine Talmant, Mirela Faighel and Marylène Jacq-Foucher for their help in selecting patients. David Laplaud and Paul Sauleau for their advices regarding data analysis. Patients and relatives for giving their time in participating in the study.


Nantes University Hospital was the study promoter. This work was supported by a Grant from Nantes University Hospital (Appel d’offre interne 2012, Grant number RC12_0264) and France Parkinson.

Compliance with ethical standards

Conflicts of interest

Authors report no disclosure relevant to the research covered in this article.

Ethical standard statement

This study was carried out in accordance with the Declaration of Helsinki, conducted with the approval of the local Ethical Committee (Comité de protection des personnes Ouest VI, France).

Supplementary material

415_2018_8789_MOESM1_ESM.xlsx (15 kb)
Supplementary material 1 (XLSX 14 kb) Supplementary Table 1. Autonomic nervous system intra and inter-component association tests. Data on ‘light-headed for some time’ and ‘when standing up’ are combined for clarity reasons, as well as data on cold and heat intolerance. A separate analysis shows that light-headed for some time and orthostatic hypotension test were significantly associated (p = 0.02)


  1. 1.
    Jain S (2011) Multi-organ autonomic dysfunction in Parkinson disease. Parkinsonism Relat Disord 17:77–83. CrossRefPubMedGoogle Scholar
  2. 2.
    McCorry LK (2007) Physiology of the autonomic nervous system. Am J Pharm Educ 71:78CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Kaufmann H, Goldstein DS (2013) Autonomic dysfunction in Parkinson disease. Handb Clin Neurol 117:259–278. CrossRefPubMedGoogle Scholar
  4. 4.
    Goldstein DS (2014) Dysautonomia in Parkinson disease. Compr Physiol 4:805–826. CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Den Hartog Jager WA, Bethlem J (1960) The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23:283–290CrossRefGoogle Scholar
  6. 6.
    Del Tredici K, Braak H (2012) Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathol 124:643–664. CrossRefPubMedGoogle Scholar
  7. 7.
    Orimo S, Uchihara T, Nakamura A et al (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131:642–650. CrossRefPubMedGoogle Scholar
  8. 8.
    Orimo S, Amino T, Itoh Y et al (2005) Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 109:583–588. CrossRefPubMedGoogle Scholar
  9. 9.
    Gelpi E, Navarro-Otano J, Tolosa E et al (2014) Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 29:1010–1018. CrossRefPubMedGoogle Scholar
  10. 10.
    Fumimura Y, Ikemura M, Saito Y et al (2007) Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in lewy body disease. J Neuropathol Exp Neurol 66:354–362. CrossRefPubMedGoogle Scholar
  11. 11.
    Ikemura M, Saito Y, Sengoku R et al (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67:945–953. CrossRefPubMedGoogle Scholar
  12. 12.
    Oyanagi K, Wakabayashi K, Ohama E et al (1990) Lewy bodies in the lower sacral parasympathetic neurons of a patient with Parkinson’s disease. Acta Neuropathol 80:558–559CrossRefPubMedGoogle Scholar
  13. 13.
    Takeda S, Yamazaki K, Miyakawa T, Arai H (1993) Parkinson’s disease with involvement of the parasympathetic ganglia. Acta Neuropathol 86:397–398CrossRefPubMedGoogle Scholar
  14. 14.
    Benarroch EE, Schmeichel AM, Sandroni P et al (2006) Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease. Neurology 66:378–383. CrossRefPubMedGoogle Scholar
  15. 15.
    Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMedGoogle Scholar
  16. 16.
    Hunter S (1985) The rostral mesencephalon in Parkinson“s disease and Alzheimer”s disease. Acta Neuropathol 68:53–58CrossRefPubMedGoogle Scholar
  17. 17.
    Wakabayashi K, Takahashi H, Takeda S et al (1988) Parkinson’s disease: the presence of Lewy bodies in Auerbach‘s and Meissner’s plexuses. Acta Neuropathol 76:217–221CrossRefPubMedGoogle Scholar
  18. 18.
    Qualman SJ, Haupt HM, Yang P, Hamilton SR (1984) Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Similarity to Parkinson’s disease. Gastroenterology 87:848–856PubMedGoogle Scholar
  19. 19.
    Annerino DM, Arshad S, Taylor GM et al (2012) Parkinson’s disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol 124:665–680. CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Beach TG, Adler CH, Sue LI et al (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702. CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Halliday GM, Blumbergs PC, Cotton RG et al (1990) Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 510:104–107CrossRefPubMedGoogle Scholar
  22. 22.
    Eadie MJ (1963) The pathology of certain medullary nuclei in parkinsonism. Brain 86:781–792CrossRefPubMedGoogle Scholar
  23. 23.
    Dabby R, Djaldetti R, Shahmurov M et al (2006) Skin biopsy for assessment of autonomic denervation in Parkinson’s disease. J Neural Transm (Vienna) 113:1169–1176. CrossRefGoogle Scholar
  24. 24.
    Leclair-Visonneau L, Clairembault T, Coron E et al (2017) REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease. Neurology 89:1612–1618. CrossRefPubMedGoogle Scholar
  25. 25.
    Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ (2004) Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord 19:1306–1312. CrossRefPubMedGoogle Scholar
  26. 26.
    Chaudhuri KR, Martinez-Martin P, Schapira AHV et al (2006) International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord 21:916–923. CrossRefPubMedGoogle Scholar
  27. 27.
    Foundation Rome (2006) Guidelines-rome iii diagnostic criteria for functional gastrointestinal disorders. J Gastrointestin Liver Dis 15:307–312Google Scholar
  28. 28.
    Duchesne M, Magy L, Richard L et al (2016) Simultaneous quantification of unmyelinated nerve fibers in sural nerve and in skin. J Neuropathol Exp Neurol 75:53–60. CrossRefPubMedGoogle Scholar
  29. 29.
    Post B, Muslimovic D, van Geloven N et al (2011) Progression and prognostic factors of motor impairment, disability and quality of life in newly diagnosed Parkinson’s disease. Mov Disord 26:449–456. CrossRefPubMedGoogle Scholar
  30. 30.
    Kotagal V, Albin RL, Müller MLTM et al (2014) Modifiable cardiovascular risk factors and axial motor impairments in Parkinson disease. Neurology 82:1514–1520. CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Fereshtehnejad S-M, Romenets SR, Anang JBM et al (2015) New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes. JAMA Neurol 72:863–873. CrossRefPubMedGoogle Scholar
  32. 32.
    Doppler K, Ebert S, Uçeyler N et al (2014) Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta Neuropathol 128:99–109. CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Goldstein DS, Holmes CS, Dendi R et al (2002) Orthostatic hypotension from sympathetic denervation in Parkinson’s disease. Neurology 58:1247–1255CrossRefPubMedGoogle Scholar
  34. 34.
    Anang JBM, Gagnon J-F, Bertrand J-A et al (2014) Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83:1253–1260. CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Kim JB, Kim B-J, Koh S-B, Park K-W (2014) Autonomic dysfunction according to disease progression in Parkinson’s disease. Parkinsonism Relat Disord 20:303–307. CrossRefPubMedGoogle Scholar
  36. 36.
    Asahina M, Mathias CJ, Katagiri A et al (2014) Sudomotor and cardiovascular dysfunction in patients with early untreated Parkinson’s disease. J Parkinsons Dis 4:385–393. PubMedGoogle Scholar
  37. 37.
    Akaogi Y, Asahina M, Yamanaka Y et al (2009) Sudomotor, skin vasomotor, and cardiovascular reflexes in 3 clinical forms of Lewy body disease. Neurology 73:59–65. CrossRefPubMedGoogle Scholar
  38. 38.
    Wakabayashi K, Mori F, Tanji K et al (2010) Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain. Acta Neuropathol 120:1–12. CrossRefPubMedGoogle Scholar
  39. 39.
    Adler CH, Beach TG (2016) Neuropathological basis of nonmotor manifestations of Parkinson’s disease. Mov Disord 31:1114–1119. CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Greffard S, Verny M, Bonnet A-M et al (2006) Motor score of the unified Parkinson disease rating scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch Neurol 63:584–588. CrossRefPubMedGoogle Scholar
  41. 41.
    Nolano M, Provitera V, Estraneo A et al (2008) Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain 131:1903–1911. CrossRefPubMedGoogle Scholar
  42. 42.
    Kass-Iliyya L, Javed S, Gosal D et al (2015) Small fiber neuropathy in Parkinson’s disease: a clinical, pathological and corneal confocal microscopy study. Parkinsonism Relat Disord 21:1454–1460. CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Zange L, Noack C, Hahn K et al (2016) Reply: skin biopsies in the differential diagnosis of parkinsonism: are we ready for simplified protocols? Brain 139:e6–e6. CrossRefPubMedGoogle Scholar
  44. 44.
    Doppler K, Volkmann J, Sommer C (2016) Skin biopsies in the differential diagnosis of parkinsonism: are we ready for simplified protocols? Brain 139:e5–e5. CrossRefPubMedGoogle Scholar
  45. 45.
    Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H (2010) Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol 119:703–713. CrossRefPubMedGoogle Scholar
  46. 46.
    Beach TG, Adler CH, Serrano G et al (2016) Prevalence of submandibular gland synucleinopathy in parkinson’s disease, dementia with Lewy bodies and other Lewy body disorders. J Parkinsons Dis 6:153–163. CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Mu L, Sobotka S, Chen J et al (2013) Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease. J Neuropathol Exp Neurol 72:119–129. CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Braak H, Sastre M, Bohl JRE et al (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421–429. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Laurène Leclair-Visonneau
    • 1
    • 2
    • 3
    • 4
    Email author
  • Laurent Magy
    • 5
  • Christelle Volteau
    • 6
  • Thomas Clairembault
    • 1
    • 2
    • 7
  • Séverine Le Dily
    • 3
  • Cécile Préterre
    • 1
    • 2
    • 3
    • 8
  • Arnaud Peyre
    • 1
    • 2
    • 3
    • 4
  • Philippe Damier
    • 2
    • 3
    • 8
  • Michel Neunlist
    • 1
    • 2
    • 7
  • Yann Péréon
    • 2
    • 4
  • Pascal Derkinderen
    • 1
    • 2
    • 3
    • 8
  1. 1.Inserm, U1235NantesFrance
  2. 2.University NantesNantesFrance
  3. 3.Inserm, CIC-04NantesFrance
  4. 4.Laboratoire d’Explorations FonctionnellesCHU NantesNantesFrance
  5. 5.Department of Neurology, Centre de Référence “Neuropathies Périphériques Rares”CHU LimogesLimogesFrance
  6. 6.Plateforme de Biométrie, Département Promotion DRCICHU NantesNantesFrance
  7. 7.Institut des Maladies de l’Appareil DigestifCHU NantesNantesFrance
  8. 8.Department of NeurologyCHU NantesNantesFrance

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