Does the Type of Multisystem Atrophy, Parkinsonism, or Cerebellar Ataxia Impact on the Nature of Sleep Disorders?

  • Luigi Ferini-StrambiEmail author
  • Sara Marelli
  • Romina Combi
Sleep (M Thorpy and M Billiard Section Editors)
Part of the following topical collections:
  1. Topical Collection on Sleep


Multiple system atrophy (MSA) is a neurodegenerative disease characterized by a combination of autonomic failure, parkinsonism, and/or cerebellar ataxia. The cause of MSA is unknown, but neuropathologically the disease is characterized by widespread α-synuclein-positive glial cytoplasmic inclusions and striatonigral and/or olivopontocerebellar neurodegeneration. Two motor phenotypes have been clinically identified: parkinsonian (MSA-P) and cerebellar (MSA-C). In order to elucidate if in addition to the motor abnormalities there are other significant differences between these two phenotypes, we performed a review of the studies on sleep disorders in the two MSA subtypes. Substantially, any significant difference in the sleep structure, as well as in the frequency and severity of the sleep disorders, has been found between MSA-P and MSA-C patients. Recent studies clearly showed similarities between the two MSA subtypes in terms of demographic distributions, natural history of the disease, and survivals. These findings suggest that although the dominant clinical presentations differ between MSA-C and MSA-P, a common pathophysiology may underlie both subtypes of MSA.


Multisystem atrophy MSA-P MSA-C Sleep disorders Stridor REM sleep behavior disorder 


Compliance with Ethical Standards

Conflict of Interest

Luigi Ferini-Strambi, Sara Marelli, and Romina Combi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Wenning GK, Stefanova N. Recent developments in multiple system atrophy. J Neurol. 2009;256:1791–808.CrossRefPubMedGoogle Scholar
  2. 2.
    Coon EA, Sletten DM, Suarez MD, Mandrekar JN, Ahlskog JE, Bower JH, et al. Clinical features and autonomic testing predict survival in multiple system atrophy. Brain. 2015;138:3623–31.CrossRefPubMedGoogle Scholar
  3. 3.
    Ferini-Strambi L, Marelli S. Sleep dysfunction in multiple system atrophy. Curr Treat Options Neurol. 2012;14:464–73.CrossRefPubMedGoogle Scholar
  4. 4.
    Ahmed Z, Asi YT, Sailer A, Lees AJ, Houlden H, Revesz T, et al. The neuropathology, pathophysiology and genetics of multiple system atrophy. Neuropathol Appl Neurobiol. 2012;38:4–24.CrossRefPubMedGoogle Scholar
  5. 5.
    Ghorayeb I, Yekhlef F, Chrysostome V, Balestre E, Bioulac B, Tison F. Sleep disorders and their determinants in multiple system atrophy. J Neurol Neurosurg Psychiatry. 2002;72:798–800.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    • Muntean ML, Sixel-Döring F, Trenkwalder C. No difference in sleep and RBD between different types of patients with multiple system atrophy: a pilot video-polysomnographical study. Sleep Disord. 2013;2013:258390. This study evaluated the two MSA subtypes paying special attention to REM sleep disturbances and periodic limb movements (PLMs). In particular, the authors analyzed the quantity of REM sleep without atonia, but they found no difference between the two subgroups.Google Scholar
  7. 7.
    Guo XY, Cao B, Lei F, Huang L, Chen K, Song W, et al. Clinical and polysomnographic features of patients with multiple system atrophy in southwest China. Sleep Breath. 2013;17:1301–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Gama RL, Távora DG, Bomfim RC, Silva CE, de Bruin VM, de Bruin PF. Sleep disturbances and brain MRI morphometry in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy—a comparative study. Parkinsonism Relat Disord. 2010;16:275–9.CrossRefPubMedGoogle Scholar
  9. 9.
    • Moreno-López C, Santamaría J, Salamero M, Del Sorbo F, Albanese A, Pellecchia MT, et al. Excessive daytime sleepiness in multiple system atrophy (SLEEMSA study). Arch Neurol. 2011;68:223–30. The SLEEMSA study evaluated the frequency and associations of EDS in 86 consecutive patients with MSA, 86 PD patients, and 86 age- and sex-matched healthy controls. EDS was present in 28% of MSA patients, in 29% of PD patients, and only in 2% of controls. EDS in MSA was related to reduced sleep efficiency and the presence of SDB.Google Scholar
  10. 10.
    Ghorayeb I, Dupouy S, Tison F, Meissner WG. Restless legs syndrome in multiple system atrophy. J Neural Transm (Vienna). 2014;121:1523–7.CrossRefGoogle Scholar
  11. 11.
    Manni R, Morini R, Martignoni E, Pacchetti C, Micieli G, Tartara A. A nocturnal sleep in multisystem atrophy with autonomic failure: polygraphic findings in ten patients. J Neurol. 1993;240:247–50.CrossRefGoogle Scholar
  12. 12.
    Wetter TC, Collado-Seidel V, Pollmächer T, Yassouridis A, Trenkwalder C. Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep. 2000;23:361–7.PubMedGoogle Scholar
  13. 13.
    Vetrugno R, Provini F, Cortelli P, Plazzi G, Lotti EM, Pierangeli G, et al. Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med. 2004;5:21–30.CrossRefPubMedGoogle Scholar
  14. 14.
    Plazzi G, Corsini R, Provini F, Pierangeli G, Martinelli P, Montagna P, et al. REM sleep behavior disorders in multiple system atrophy. Neurology. 1997;48:1094–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Nam H, Hong YH, Kwon HM, Cho J. Does multiple system atrophy itself affect sleep structure? Neurologist. 2009;15:274–6.CrossRefPubMedGoogle Scholar
  16. 16.
    • De Cock VC, Debs R, Oudiette D, Leu S, Radji F, Tiberge M, et al. The improvement of movement and speech during rapid eye movement sleep behaviour disorder in multiple system atrophy. Brain. 2011;134:856–62. This interesting study showed that motor control was transiently improved during RBD episodes in MSA patients, as well as in PD patients. The rate of improvement was similar in the two subtypes of MSA.Google Scholar
  17. 17.
    Shimohata T, Nakayama H, Tomita M, Ozawa T, Nishizawa M. Daytime sleepiness in Japanese patients with multiple system atrophy: prevalence and determinants. BMC Neurol. 2012;12:130.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Benarroch EE, Schmeichel AM, Sandroni P, Low PA, Parisi JE. Involvement of hypocretin neurons in multiple system atrophy. Acta Neuropathol. 2007;113:75–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Martinez-Rodriguez JE, Seppi K, Cardozo A, Iranzo A, Stampfer-Kountchev M, Wenning G, et al. Cerebrospinal fluid hypocretin-1 levels in multiple system atrophy. Mov Disord. 2007;22:1822–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Arnulf I. Excessive daytime sleepiness in Parkinsonism. Sleep Med Rev. 2005;9:185–200.CrossRefPubMedGoogle Scholar
  21. 21.
    Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553–62.CrossRefPubMedGoogle Scholar
  22. 22.
    Drouot X, Moutereau S, Nguyen JP, Lefaucheur JP, Créange A, Remy P, et al. Low levels of ventricular CSF orexin/hypocretin in advanced PD. Neurology. 2003;61:540–3.CrossRefPubMedGoogle Scholar
  23. 23.
    Abdo WF, Bloem BR, Kremer HP, Lammers GJ, Verbeek MM, Overeem S. CSF hypocretin-1 levels are normal in multiple-system atrophy. Parkinsonism Relat Disord. 2008;14:342–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Benarroch EE, Schmeichel AM, Sandroni P, Low PA, Parisi JE. Differential involvement of hypothalamic vasopressin neurons in multiple system atrophy. Brain. 2006;129:2688–96.CrossRefPubMedGoogle Scholar
  25. 25.
    Högl B, Seppi K, Brandauer E, Wenning G, Poewe W. Irresistible onset of sleep during acute levodopa challenge in a patient with multiple system atrophy (MSA): placebo-controlled, polysomnographic case report. Mov Disord. 2001;16:1177–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Seppi K, Högl B, Diem A, Peralta C, Wenning GK, Poewe W. Levodopa-induced sleepiness in the Parkinson variant of multiple system atrophy. Mov Disord. 2006;21:1281–3.CrossRefPubMedGoogle Scholar
  27. 27.
    • Gaig C, Iranzo A. Sleep-disordered breathing in neurodegenerative diseases. Curr Neurol Neurosci Rep. 2012;12:205–17. This is an excellent review on sleep disordered breathing in neurodegenerative diseases.Google Scholar
  28. 28.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670–6.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Glass GA, Josephs KA, Ahlskog JE. Respiratory insufficiency as the primary presenting symptom of multiple system atrophy. Arch Neurol. 2006;63:978–81.CrossRefPubMedGoogle Scholar
  30. 30.
    Uzawa A, Sakakibara R, Tamura N, Asahina M, Yamanaka Y, Uchiyama T, et al. Laryngeal abductor paralysis can be a solitary manifestation of multiple system atrophy. J Neurol Neurosurg Psychiatry. 2005;76:1739–41.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    • Koo DL, Lee JY, Joo EY, Hong SB, Nam H. Acoustic characteristics of stridor in multiple system atrophy. PLoS One. 2016;11:e0153935. This study classified the types of stridor by sound analysis in 22 MSA patients. The outcome of patients with rhythmic waveform was significantly less favorable than the outcome of patients with semirhythmic waveform, but the phenotype of MSA (MSA-P vs MSA-C) did not significantly differ between rhythmic and semirhythmic waveform groups.Google Scholar
  32. 32.
    Iranzo A. Sleep and breathing in multiple system atrophy. Curr Treat Options Neurol. 2007;9:347–53.CrossRefPubMedGoogle Scholar
  33. 33.
    Garcia-Sanchez A, Fernandez-Navarro I, Garcia-Rio F. Central apneas and REM sleep behavior disorder as an initial presentation of multiple system atrophy. J Clin Sleep Med. 2016;12:267–70.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Suzuki M, Saigusa H, Shibasaki K. Multiple system atrophy manifesting as complex sleep-disordered breathing. Auris Nasus Larynx. 2010;37:110–3.CrossRefPubMedGoogle Scholar
  35. 35.
    Vincken W, Gauthier S, Dollfuss R, Hanson RE, Darauay CM, Cosio MG. Involvement of upper-airway muscles in extrapyramidal disorders. A cause of airflow limitation. N Engl J Med. 1984;16:438–42.CrossRefGoogle Scholar
  36. 36.
    Stanzani-Maserati M, Gallassi R, Calandra-Buonaura G, Alessandria M, Oppi F, Poda R, et al. Cognitive and sleep features of multiple system atrophy: review and prospective study. Eur Neurol. 2014;72:349–59.CrossRefPubMedGoogle Scholar
  37. 37.
    Schenck CH, Bundlie SR, Patterson AL, Mahowald MW. Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. JAMA. 1987;257:1786–9.CrossRefPubMedGoogle Scholar
  38. 38.
    • Iranzo A, Santamaria J, Tolosa E. Idiopathic rapid eye movement sleep behavior disorder: diagnosis, management, and the need for neuroprotective interventions. Lancet Neurol. 2016;15:405–19. This is an extensive review that considers all the clinical and diagnostic aspects of idiopathic RBD (iRBD). The authors also report the aspects that should be considered in future trials of neuroprotective strategies for iRBD patients.CrossRefPubMedGoogle Scholar
  39. 39.
    Palma JA, Fernandez-Cordon C, Coon EA, Low PA, Miglis MG, Jaradeh S, et al. Prevalence of REM sleep behavior disorder in multiple system atrophy: a multicenter study and meta-analysis. Clin Auton Res. 2015;25:69–75.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Plazzi G, Cortelli P, Montagna P, De Monte A, Corsini R, Contin M, et al. REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure. J Neurol Neurosurg Psychiatry. 1998;64:683–5.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kashihara K, Ohno M, Kawada S, Imamura T. Frequent nocturnal vocalization in pure autonomic failure. J Int Med Res. 2008;36:489–95.CrossRefPubMedGoogle Scholar
  42. 42.
    Nomura T, Inoue Y, Högl B, Uemura Y, Yasui K, Sasai T, et al. Comparison of the clinical features of rapid eye movement sleep behavior disorder in patients with Parkinson’s disease and multiple system atrophy. Psychiatry Clin Neurosci. 2011;65:264–71.CrossRefPubMedGoogle Scholar
  43. 43.
    Frauscher B, Iranzo A, Gaig C, Gschliesser V, Guaita M, Raffelseder V, et al. Normative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder. Sleep. 2012;35:835–47.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sixel-Döring F, Schweitzer M, Mollenhauer B, Trenkwalder C. Intraindividual variability of REM sleep behavior disorder in Parkinson’s disease: a comparative assessment using a new REM sleep behavior disorder severity scale (RBDSS) for clinical routine. J Clin Sleep Med. 2011;7:75–80.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Mayer G, Bitterlich M, Kuwert T, Ritt P, Stefan H. Ictal SPECT in patients with rapid eye movement sleep behaviour disorder. Brain. 2015;138:1263–70.CrossRefPubMedGoogle Scholar
  46. 46.
    Abbott SM, Videnovic A. Sleep disorders in atypical Parkinsonism. Mov Disord Clin Pract. 2014;1:89–96.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Roncevic D, Palma JA, Martinez J, Goulding N, Norcliffe-Kaufmann L, Kaufmann H. Cerebellar and parkinsonian phenotypes in multiple system atrophy: similarities, differences and survival. J Neural Transm (Vienna). 2014;121:507–12.CrossRefGoogle Scholar
  48. 48.
    • Low PA, Reich SG, Jankovic J, Shults CW, Stern MB, Novak P, et al. Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 2015;14:710–9. This prospective study evaluated 126 patients with MSA-P and 49 with MSA-C and showed that natural histories of the two subtypes are similar.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Luigi Ferini-Strambi
    • 1
    Email author
  • Sara Marelli
    • 1
  • Romina Combi
    • 2
  1. 1.Department of Clinical NeurosciencesSan Raffaele Scientific Institute, Sleep Disorders Center, Università Vita-Salute San RaffaeleMilanItaly
  2. 2.Department of Surgery and Translational MedicineUniversità of Milano-BicoccaMilanItaly

Personalised recommendations