Journal of Neurology

, Volume 264, Issue 11, pp 2249–2257 | Cite as

Non-motor multiple system atrophy associated with sudden death: pathological observations of autonomic nuclei

  • Yuichi Riku
  • Hirohisa Watanabe
  • Maya Mimuro
  • Yasushi Iwasaki
  • Mizuki Ito
  • Masahisa Katsuno
  • Gen Sobue
  • Mari YoshidaEmail author
Original Communication


Multiple system atrophy (MSA) manifests as a combination of dysautonomia and motor symptoms/signs. However, rare cases presenting with autonomic failures in absence of motor symptoms/signs until their deaths have been reported and are referred to as non-motor MSA. To clarify pathological findings underlying non-motor MSA patients, we analyzed consecutively autopsied 161 patients with MSA. In results, four patients were identified as having non-motor MSA, who showed isolated autonomic disorders throughout their lives and had minimal pathological changes in the motor systems. We also identified two patients with pathologically minimal MSA, who had minimal pathological involvement in the motor systems and presented with definite parkinsonism and dysautonomia. Survival durations of the non-motor MSA patients were much shorter (1.3–2.0 years) than those of the classical MSA patients (3.0–7.0 years), and the causes of death were all sudden death. The medullary serotonergic neurons were severely involved in the non-motor MSA patients in comparison with the classical MSA patients. Also, one of the pathologically minimal MSA patients had died suddenly and exhibited marked involvement of the medullary serotonergic neurons. The involvement of the medullary catecholaminergic or cholinergic neurons did not differ in severities among the groups. We conclude that non-motor MSA may be a pathological variant of MSA that preferentially involves the medullary serotonergic neurons and autonomic systems in association with poor prognosis.


Multiple system atrophy Autopsy Autonomic failure Sudden death 


Author contributions

Study concept and design: Yuichi Riku, Hirohisa Watanabe, Mari Yoshida, and Gen Sobue. Acquisition of data: Yuichi Riku, Maya Mimuro, Hirohisa Watanabe, and Mari Yoshida. Analysis and interpretation of data: Yuichi Riku, Hirohisa Watanabe, Masahisa Katsuno, Mari Yoshida, and Gen Sobue. Drafting of the manuscript: Yuichi Riku. Administrative, technical, and material support: Yuichi Riku, Maya Mimuro, and Yasushi Iwasaki. Study supervision: Mari Yoshida, Hirohisa Watanabe, and Gen Sobue. We give special thanks to all the patients, their families, and the staff in the affiliated hospitals for providing the autopsy materials and clinical data.

Compliance with ethical standards

Conflict of interest

All authors declared that they have no potential conflict of interest.

Ethical standards

The study was performed in accordance with the research ethical committees of Aichi Medical University.


This work was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan.

Supplementary material

415_2017_8604_MOESM1_ESM.pdf (143 kb)
Supplementary material 1 (PDF 142 kb)


  1. 1.
    Wenning GK, Colosimo C, Geser F, Poewe W (2004) Multiple system atrophy. Lancet Neurol 3:93–103CrossRefPubMedGoogle Scholar
  2. 2.
    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 12:264–274CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    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 71:670–676CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Jecmenica-Lukic M, Poewe W, Tolosa E, Wenning GK (2012) Premotor signs and symptoms of multiple system atrophy. Lancet Neurol 11:361–368CrossRefPubMedGoogle Scholar
  5. 5.
    Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, Aiba I, Abe Y, Tamakoshi A, Doyu M, Hirayama M, Sobue G (2002) Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 125:1070–1083CrossRefPubMedGoogle Scholar
  6. 6.
    Gaig C, Iranzo A, Tolosa E, Vilaseca I, Rey MJ, Santamaria J (2008) Pathological description of a non-motor variant of multiple system atrophy. J Neurol Neurosurg Psychiatry 79:1399–1400CrossRefPubMedGoogle Scholar
  7. 7.
    Bannister R, Gibson W, Michaels L, Oppenheimer DR (1981) Laryngeal abductor paralysis in multiple system atrophy. A report on three necropsied cases, with observations on the laryngeal muscles and the nuclei ambigui. Brain 104:351–368CrossRefPubMedGoogle Scholar
  8. 8.
    Mochizuki A, Mizusawa H, Ohkoshi N, Yoshizawa K, Komatsuzaki Y, Inoue K, Kanazawa I (1992) Argentophilic intracytoplasmic inclusions in multiple system atrophy. J Neurol 239:311–316CrossRefPubMedGoogle Scholar
  9. 9.
    Hughes RG, Gibbin KP, Lowe J (1998) Vocal fold abductor paralysis as a solitary and fatal manifestation of multiple system atrophy. J Laryngol Otol 112:177–178PubMedGoogle Scholar
  10. 10.
    Jellinger KA, Seppi K, Wenning GK (2005) Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 20(Suppl 12):S29–S36CrossRefPubMedGoogle Scholar
  11. 11.
    Tada M, Onodera O, Tada M, Ozawa T, Piao YS, Kakita A, Takahashi H, Nishizawa M (2007) Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy. Arch Neurol 64:256–260CrossRefPubMedGoogle Scholar
  12. 12.
    Groh WJ, Groh MR, Saha C, Kincaid JC, Simmons Z, Ciafaloni E, Pourmand R, Otten RF, Bhakta D, Nair GV, Marashdeh MM, Zipes DP, Pascuzzi RM (2008) Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 358:2688–2697CrossRefPubMedGoogle Scholar
  13. 13.
    Tada M, Kakita A, Toyoshima Y, Onodera O, Ozawa T, Morita T, Nishizawa M, Takahashi H (2009) Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death. Brain 132:1810–1819CrossRefPubMedGoogle Scholar
  14. 14.
    Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, Kakuta Y, Yamanouchi H, Murayama S (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918CrossRefPubMedGoogle Scholar
  15. 15.
    McKeith IG, 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) Consortium on DLB: diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 65:1863–1872CrossRefPubMedGoogle Scholar
  16. 16.
    Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT, National institute on aging (2012) Alzheimer’s association: national institute on aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11CrossRefPubMedGoogle Scholar
  17. 17.
    Benarroch EE, Schmeichel AM, Parisi JE (2000) Involvement of the ventrolateral medulla in parkinsonism with autonomic failure. Neurology 54:963–968CrossRefPubMedGoogle Scholar
  18. 18.
    Olszewski J, Baxter D (1982) Serial semischematic drawings and photomicrographs. Cytoarchitecture of the human brain stem, 2nd edn. Karger, Basel, pp 17–50Google Scholar
  19. 19.
    Martin GF, Holstege G, Mehler WR (1995) Reticular formation of the pons and medulla. In: Paxinos G (ed) Atlas of the human brainstem. Academic Press, San Diego, pp 203–220Google Scholar
  20. 20.
    Kingsbury AE, Bandopadhyay R, Silveira-Moriyama L, Ayling H, Kallis C, Sterlacci W, Maeir H, Poewe W, Lees AJ (2010) Brain stem pathology in Parkinson’s disease: an evaluation of the Braak staging model. Mov Disord 25:2508–2515CrossRefPubMedGoogle Scholar
  21. 21.
    Hilaire G, Voituron N, Menuet C, Ichiyama RM, Subramanian HH, Dutschmann M (2010) The role of serotonin in respiratory function and dysfunction. Respir Physiol Neurobiol 174:76–88CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Guyenet PG, Bayliss DA (2015) Neural control of breathing and CO2 homeostasis. Neuron 87:946–961CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Benarroch EE, Smithson IL, Low PA, Parisi JE (1998) Depletion of catecholaminergic neurons of the rostral ventrolateral medulla in multiple system atrophy with autonomic failure. Ann Neurol 43:156–163CrossRefPubMedGoogle Scholar
  24. 24.
    Machado BH, Brody MJ (1988) Role of the nucleus ambiguus in the regulation of heart rate and arterial pressure. Hypertension 11:602–607CrossRefPubMedGoogle Scholar
  25. 25.
    Irnaten M, Aicher SA, Wang J, Venkatesan P, Evans C, Baxi S, Mendelowitz D (2003) μ-opioid receptors are located postsynaptically and endomorphin-1 inhibits voltage-gated calcium currents in premotor cardiac parasympathetic neurons in the rat nucleus ambiguus. Neuroscience 116:573–582CrossRefPubMedGoogle Scholar
  26. 26.
    Bogousslavsky J, Khurana R, Deruaz JP, Hornung JP, Regli F, Janzer R, Perret C (1990) Respiratory failure and unilateral caudal brainstem infarction. Ann Neurol 28:668–673CrossRefPubMedGoogle Scholar
  27. 27.
    Ling H, Asi YT, Petrovic IN, Ahmed Z, Prashanth LK, Hazrati LN, Nishizawa M, Ozawa T, Lang A, Lees AJ, Revesz T, Holton JL (2015) Minimal change multiple system atrophy: an aggressive variant? Mov Disord 30:960–967CrossRefPubMedGoogle Scholar
  28. 28.
    Parkkinen L, Hartikainen P, Alafuzoff I (2007) Abundant glial alpha-synuclein pathology in a case without overt clinical symptoms. Clin Neuropathol 26:276–283CrossRefPubMedGoogle Scholar
  29. 29.
    Fujishiro H, Ahn TB, Frigerio R, DelleDonne A, Josephs KA, Parisi JE, Eric Ahlskog J, Dickson DW (2008) Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy? Acta Neuropathol 116:269–275CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Rodriguez-Diehl R, Rey MJ, Gironell A, Martinez-Saez E, Ferrer I, Sánchez-Valle R, Jagüe J, Nos C, Gelpi E (2012) “Pre-clinical” MSA in definite Creutzfeldt-Jakob disease. Neuropathology 32:158–163CrossRefPubMedGoogle Scholar
  31. 31.
    Kon T, Mori F, Tanji K, Miki Y, Wakabayashi K (2013) An autopsy case of preclinical multiple system atrophy (MSA-C). Neuropathology 33:667–672CrossRefPubMedGoogle Scholar
  32. 32.
    Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, Movement Disorder Society UPDRS Revision Task Force (2008) movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23:2129–2170CrossRefPubMedGoogle Scholar
  33. 33.
    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, International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome (1997) The ataxia neuropharmacology committee of the World Federation of Neurology. J Neurol Sci 145:205–211CrossRefPubMedGoogle Scholar
  34. 34.
    Wenning GK, Tison F, Seppi K, Sampaio C, Diem A, Yekhlef F, Ghorayeb I, Ory F, Galitzky M, Scaravilli T, Bozi M, Colosimo C, Gilman S, Shults CW, Quinn NP, Rascol O, Poewe W, Multiple System Atrophy Study Group (2004) Development and validation of the unified multiple system atrophy rating scale (UMSARS). Mov Disord 19:1391–1402CrossRefPubMedGoogle Scholar
  35. 35.
    Siderowf A, Lang AE (2012) Premotor Parkinson’s disease: concepts and definitions. Mov Disord 27:608–616CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL, Revesz T (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127:2657–2671CrossRefPubMedGoogle Scholar
  37. 37.
    Plazzi G, Corsini R, Provini F (1997) REM sleep behavior disorders in multiple system atrophy. Neurology 48:1094–1097CrossRefPubMedGoogle Scholar
  38. 38.
    Orimo S, Suzuki M, Inaba A, Mizusawa H (2012) 123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord 18:494–500CrossRefPubMedGoogle Scholar
  39. 39.
    Iodice V, Lipp A, Ahlskog JE, Sandroni P, Fealey RD, Parisi JE, Matsumoto JY, Benarroch EE, Kimpinski K, Singer W, Gehrking TL, Gehrking JA, Sletten DM, Schmeichel AM, Bower JH, Gilman S, Figueroa J, Low PA (2012) Autopsy confirmed multiple system atrophy cases: mayo experience and role of autonomic function tests. J Neurol Neurosurg Psychiatry 83:453–459CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Institute for Medical Science of AgingAichi Medical UniversityNagakuteJapan

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