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The Diagnosis and Natural History of Multiple System Atrophy, Cerebellar Type

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Abstract

The objective of this study was to identify key features differentiating multiple system atrophy cerebellar type (MSA-C) from idiopathic late-onset cerebellar ataxia (ILOCA). We reviewed records of patients seen in the Massachusetts General Hospital Ataxia Unit between 1992 and 2013 with consensus criteria diagnoses of MSA-C or ILOCA. Twelve patients had definite MSA-C, 53 had possible/probable MSA-C, and 12 had ILOCA. Autonomic features, specifically urinary urgency, frequency, and incontinence with erectile dysfunction in males, differentiated MSA-C from ILOCA throughout the disease course (p = 0.005). Orthostatic hypotension developed later and differentiated MSA-C from ILOCA (p < 0.01). REM sleep behavior disorder (RBD) occurred early in possible/probable MSA-C (p < 0.01). Late MSA-C included pathologic laughing and crying (PLC, p < 0.01), bradykinesia (p = 0.01), and corticospinal findings (p = 0.01). MRI distinguished MSA-C from ILOCA by atrophy of the brainstem (p < 0.01) and middle cerebellar peduncles (MCP, p = 0.02). MSA-C progressed faster than ILOCA: by 6 years, MSA-C walker dependency was 100 % and ILOCA 33 %. MSA-C survival was 8.4 ± 2.5 years. Mean length of ILOCA illness to date is 15.9 ± 6.4 years. A sporadic onset, insidiously developing cerebellar syndrome in midlife, with autonomic features of otherwise unexplained bladder dysfunction with or without erectile dysfunction in males, and atrophy of the cerebellum, brainstem, and MCP points strongly to MSA-C. RBD and postural hypotension confirm the diagnosis. Extrapyramidal findings, corticospinal tract signs, and PLC are helpful but not necessary for diagnosis. Clarity in early MSA-C diagnosis can prevent unnecessary investigations and facilitate therapeutic trials.

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References

  1. Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Quinn N. Multiple system atrophy—the nature of the beast. J Neurol Neurosurg Psychiatry. 1989;52(Suppl):78–89.

    Article  PubMed Central  Google Scholar 

  3. Wenning GK, Stefanova N. Recent developments in multiple system atrophy. J Neurol. 2009;256(11):1791–808.

    Article  PubMed  Google Scholar 

  4. Saito Y, Matsuoka Y, Takahashi A, Ohno Y. Survival of patients with multiple system atrophy. Intern Med. 1994;33(6):321–5.

    Article  CAS  PubMed  Google Scholar 

  5. Schrag A, Wenning GK, Quinn N, Ben-Shlomo Y. Survival in multiple system atrophy. Mov Disord. 2008;23(2):294–6.

    Article  PubMed  Google Scholar 

  6. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci. 1989;94(1–3):79–100.

    Article  CAS  PubMed  Google Scholar 

  7. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett. 1998;249(2–3):180–2.

    Article  CAS  PubMed  Google Scholar 

  8. Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol. 1998;44(3):415–22.

    Article  CAS  PubMed  Google Scholar 

  9. Spillantini MG, Crowther RA, Jakes R, et al. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett. 1998;251(3):205–8.

    Article  CAS  PubMed  Google Scholar 

  10. Fellner L, Wenning GK, Stefanova N. Models of multiple system atrophy. Curr Top Behav Neurosci. 2013.

  11. Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. 1999;163(1):94–8.

    Article  CAS  PubMed  Google Scholar 

  12. May S, Gilman S, Sowell BB, et al. Potential outcome measures and trial design issues for multiple system atrophy. Mov Disord. 2007;22(16):2371–7.

    Article  PubMed  Google Scholar 

  13. Geser F, Seppi K, Stampfer-Kountchev M, et al. The European Multiple System Atrophy-Study Group (EMSA-SG). J Neural Transm. 2005;112(12):1677–86.

    Article  CAS  PubMed  Google Scholar 

  14. Gilman S, May SJ, Shults CW, et al. The North American Multiple System Atrophy Study Group. J Neural Transm. 2005;112(12):1687–94.

    Article  CAS  PubMed  Google Scholar 

  15. Wenning GK, Ben Shlomo Y, Magalhaes M, et al. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain. 1994;117(Pt 4):835–45.

    Article  PubMed  Google Scholar 

  16. Köllensperger M, Geser F, Ndayisaba J-P, et al. Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov Disord. 2010;25(15):2604–12.

    Article  PubMed  Google Scholar 

  17. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 2013;12(3):264–74.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dickson DW. Parkinson’s disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med. 2012;2(8):1–15.

    Article  Google Scholar 

  19. Joutsa J, Gardberg M, Röyttä M, Kaasinen V. Diagnostic accuracy of parkinsonism syndromes by general neurologists. Parkinsonism Relat Disord. 2014;20(8):804–4.

    Article  Google Scholar 

  20. Roncevic D, Palma J-A, Martinez J, et al. Cerebellar and parkinsonian phenotypes in multiple system atrophy: similarities, differences and survival. J Neural Transm. 2014;121(5):507–12.

    Article  PubMed  Google Scholar 

  21. Vallelunga A, Ragusa M, Di Mauro S, et al. Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and multiple system atrophy. Front Cell Neurosci. 2014;8:156.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jecmenica-Lukic M, Petrovic IN, Pekmezovic T, Kostic VS. Clinical outcomes of two main variants of progressive supranuclear palsy and multiple system atrophy: a prospective natural history study. J Neurol. 2014;261(8):1575–83.

    Article  PubMed  Google Scholar 

  23. Sako W, Murakami N, Izumi Y, Kaji R. The difference in putamen volume between MSA and PD: evidence from a meta-analysis. Parkinsonism Relat Disord. 2014;20(8):873–7.

    Article  PubMed  Google Scholar 

  24. Low PA, Reich SG, Jankovic J, et al. Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 2015;14(7):710–9.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, et al. Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain. 2002;125(Pt 5):1070–83.

    Article  PubMed  Google Scholar 

  26. Kasahara S, Miki Y, Kanagaki M, Kondo T, Yamamoto A, Morimoto E, et al. “Hot cross bun” sign in multiple system atrophy with predominant cerebellar ataxia: a comparison between proton density-weighted imaging and T2-weighted imaging. Eur J Radiol. 2012;81:2848–52.

    Article  PubMed  Google Scholar 

  27. Yabe I, Soma H, Takei A, Fujiki N, Yanagihara T, Sasaki H. MSA-C is the redominant clinical phenotype of MSA in Japan: analysis of 142 patients with probable MSA. J Neurol Sci. 2006;249(2):115–21.

    Article  PubMed  Google Scholar 

  28. Lin DJ, Hermann KL, Schmahmann JD. Multiple system atrophy of the cerebellar type: clinical state of the art. Mov Disord. 2014;29(3):294–304.

    Article  PubMed  Google Scholar 

  29. Klockgether T. Sporadic ataxia with adult onset: classification and diagnostic criteria. Lancet Neurol. 2010;9(1):94–104.

    Article  CAS  PubMed  Google Scholar 

  30. Manto M, Gruol D, Schmahmann J, et al., editors. Handbook of the cerebellum and cerebellar disorders. New York: Springer; 2012.

    Google Scholar 

  31. Harding AE. “Idiopathic” late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci. 1981;51(2):259–71.

    Article  CAS  PubMed  Google Scholar 

  32. Abele M, Minnerop M, Urbach H, et al. Sporadic adult onset ataxia of unknown etiology. J Neurol. 2007;254(10):1384–9.

    Article  CAS  PubMed  Google Scholar 

  33. Jecmenica-Lukic M, Poewe W, Tolosa E, Wenning GK. Premotor signs and symptoms of multiple system atrophy. Lancet Neurol. 2012;11(4):361–8.

    Article  PubMed  Google Scholar 

  34. Abele M, Burk K, Schols L, et al. The aetiology of sporadic adult-onset ataxia. Brain. 2002;125(Pt 5):961–8.

    Article  CAS  PubMed  Google Scholar 

  35. Gilman S, Little R, Johanns J, et al. Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy. Neurology. 2000;55(4):527–32.

    Article  CAS  PubMed  Google Scholar 

  36. Factor SA, Qian J, Lava NS, et al. False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy. Ann Neurol. 2005;57(3):462–3.

    Article  PubMed  Google Scholar 

  37. Munhoz RP, Teive HA, Raskin S, Werneck LC. CTA/CTG expansions at the SCA 8 locus in multiple system atrophy. Clin Neurol Neurosurg. 2009;111(2):208–10.

    Article  PubMed  Google Scholar 

  38. Wenning GK, Kraft E, Beck RW, et al. Cerebellar presentation of multiple system atrophy. Mov Disord. 1997;12(1):115–7.

    Article  CAS  PubMed  Google Scholar 

  39. Schols L, Szymanski S, Peters S, et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet. 2000;107(2):132–7.

    Article  CAS  PubMed  Google Scholar 

  40. Kerber KA, Jen JC, Perlman S, Baloh RW. Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. J Neurol Sci. 2005;238(1–2):41–5.

    Article  CAS  PubMed  Google Scholar 

  41. Brussino A, Gellera C, Saluto A, et al. FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology. 2005;64(1):145–7.

    Article  CAS  PubMed  Google Scholar 

  42. Wardle M, Majounie E, Muzaimi MB, et al. The genetic aetiology of late-onset chronic progressive cerebellar ataxia. A population-based study. J Neurol. 2009;256(3):343–8.

    Article  PubMed  Google Scholar 

  43. Margolin DH, Kousi M, Chan Y-M, et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med. 2013;368(21):1992–2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pierce SB, Walsh T, Chisholm KM, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault syndrome. Am J Hum Genet. 2010;87(2):282–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lieber DS, Vafai SB, Horton LC, et al. Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease. BMC Med Genet. 2012;13:3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lieber DS, Calvo SE, Shanahan K, et al. Targeted exome sequencing of suspected mitochondrial disorders. Neurology. 2013;80(19):1762–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lieber DS, Hershman SG, Slate NG, et al. Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency. BMC Med Genet. 2014;15:30.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Figueroa JJ, Singer W, Parsaik A, et al. Multiple system atrophy: prognostic indicators of survival. Mov Disord. 2014;29(9):1151–7.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Iodice V, Lipp A, Ahlskog JE, et al. Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests. J Neurol Neurosurg Psychiatry. 2012;83(4):453–9.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Iranzo A, Santamaría J, Rye DB, et al. Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology. 2005;65(2):247–52.

    Article  CAS  PubMed  Google Scholar 

  51. Muntean M-L, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ghorayeb I, Bioulac B, Tison F. Sleep disorders in multiple system atrophy. J Neural Transm. 2005;112(12):1669–75.

    Article  CAS  PubMed  Google Scholar 

  53. Weisman D, McKeith I. Dementia with Lewy bodies. Semin Neurol. 2007;27(1):42–7.

    Article  PubMed  Google Scholar 

  54. Parvizi J, Joseph J, Press DZ, Schmahmann JD. Pathological laughter and crying in patients with multiple system atrophy-cerebellar type. Mov Disord. 2007;22(6):798–803.

    Article  PubMed  Google Scholar 

  55. Magalhaes M, Wenning GK, Daniel SE, Quinn NP. Autonomic dysfunction in pathologically confirmed multiple system atrophy and idiopathic Parkinson’s disease—a retrospective comparison. Acta Neurol Scand. 1995;91(2):98–102.

    Article  CAS  PubMed  Google Scholar 

  56. Silber MH, Levine S. Stridor and death in multiple system atrophy. Mov Disord. 2000;15(4):699–704.

    Article  CAS  PubMed  Google Scholar 

  57. Yamaguchi M, Arai K, Asahina M, Hattori T. Laryngeal stridor in multiple system atrophy. Eur Neurol. 2003;49(3):154–9.

    Article  PubMed  Google Scholar 

  58. Wenning GK, Ben-Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiatry. 1995;58:160–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Stankovic I, Krismer F, Jesic A, et al. Cognitive impairment in multiple system atrophy: a position statement by the neuropsychology task force of the MDS multiple system atrophy (MODIMSA) study group. Mov Disord. 2014;29(7):857–67.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Manto M, Mariën P. Schmahmann's syndrome - identification of the third cornerstone of clinical ataxiology. Cerebellum Ataxias. 2015;2:2.

  61. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(Pt 4):561–79.

    Article  PubMed  Google Scholar 

  62. Schmahmann JD. The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol Rev. 2010;20(3):236–60.

    Article  PubMed  Google Scholar 

  63. Iseki E, Takayama N, Marui W, et al. Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains. J Neurol Sci. 2002;195(1):85–91.

    Article  PubMed  Google Scholar 

  64. Burk K, Globas C, Wahl T, et al. MRI-based volumetric differentiation of sporadic cerebellar ataxia. Brain. 2004;127(Pt 1):175–81.

    Article  CAS  PubMed  Google Scholar 

  65. Bürk K, Bühring U, Schulz JB, et al. Clinical and magnetic resonance imaging characteristics of sporadic cerebellar ataxia. Arch Neurol. 2005;62(6):981–5.

    Article  PubMed  Google Scholar 

  66. Konagaya M, Konagaya Y, Iida M. Clinical and magnetic resonance imaging study of extrapyramidal symptoms in multiple system atrophy. J Neurol Neurosurg Psychiatry. 1994;57(12):1528–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Naka H, Ohshita T, Murata Y, et al. Characteristic MRI findings in multiple system atrophy: comparison of the three subtypes. Neuroradiology. 2002;44(3):204–9.

    Article  CAS  PubMed  Google Scholar 

  68. Schrag A, Kingsley D, Phatouros C, et al. Clinical usefulness of magnetic resonance imaging in multiple system atrophy. J Neurol Neurosurg Psychiatry. 1998;65(1):65–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schrag A, Good CD, Miszkiel K, et al. Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology. 2000;54(3):697–702.

    Article  CAS  PubMed  Google Scholar 

  70. Lee W-H, Lee C-C, Shyu W-C, et al. Hyperintense putaminal rim sign is not a hallmark of multiple system atrophy at 3T. AJNR Am J Neuroradiol. 2005;26(9):2238–42.

    PubMed  Google Scholar 

  71. Burk K, Skalej M, Dichgans J. Pontine MRI hyperintensities (“the cross sign”) are not pathognomonic for multiple system atrophy (MSA). Mov Disord. 2001;16(3):535.

    Article  CAS  PubMed  Google Scholar 

  72. Horimoto Y, Aiba I, Yasuda T, et al. Longitudinal MRI study of multiple system atrophy—when do the findings appear, and what is the course? J Neurol. 2002;249(7):847–54.

    Article  PubMed  Google Scholar 

  73. Prakash N, Hageman N, Hua X, et al. Patterns of fractional anisotropy changes in white matter of cerebellar peduncles distinguish spinocerebellar ataxia-1 from multiple system atrophy and other ataxia syndromes. NeuroImage. 2009;47 Suppl 2:T72–81.

    Article  PubMed  Google Scholar 

  74. Lirng J-F, Wang P-S, Chen H-C, et al. Differences between spinocerebellar ataxias and multiple system atrophy-cerebellar type on proton magnetic resonance spectroscopy. PLoS ONE. 2012;7(10), e47925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Oz G, Iltis I, Hutter D, et al. Distinct neurochemical profiles of spinocerebellar ataxias 1, 2, 6, and cerebellar multiple system atrophy. Cerebellum. 2011;10(2):208–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Boesch SM, Wolf C, Seppi K, et al. Differentiation of SCA2 from MSA-C using proton magnetic resonance spectroscopic imaging. J Magn Reson Imaging. 2007;25(3):564–9.

    Article  PubMed  Google Scholar 

  77. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16(3):367–78.

    Article  PubMed  Google Scholar 

  78. Manto M-U, Pandolfo M, editors. The cerebellum and its disorders. Cambridge: Cambridge University Press; 2002.

    Google Scholar 

  79. Pedroso JL, Braga-Neto P, Felício AC, et al. Sleep disorders in cerebellar ataxias. Arq Neuropsiquiatr. 2011;69(2A):253–7.

    Article  PubMed  Google Scholar 

  80. Kuzdas-Wood D, Stefanova N, Jellinger KA, et al. Towards translational therapies for multiple system atrophy. Prog Neurobiol. 2014;118:19–35.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Fogel BL, Lee H, Deignan JL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71(10):1237–46.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65(5):610–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. The Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med. 2013;369(3):233–44.

    Article  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the helpful discussions regarding statistical analysis with Hang Lee, PhD of the MGH Department of Biostatistics; the assistance of Jason MacMore, BA; and the clinical care and coordination of the patients in this study by Marygrace Neal, MA. The neuropathological studies were performed, and reports generated, by Dr. E. Tessa Hedley-Whyte and Dr. Matthew P. Frosch of the MGH Department of Neuropathology. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health-care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health-care centers, or the National Institutes of Health. This work was supported in part by the Birmingham Foundation and the MINDlink Foundation. This study is dedicated to our patients in the MGH Ataxia Unit and their families, without whose commitment to research into MSA-C and related ataxias this study could not have been performed.

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  1. Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    David J. Lin, Katherine L. Hermann & Jeremy D. Schmahmann

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  1. David J. Lin
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Lin, D.J., Hermann, K.L. & Schmahmann, J.D. The Diagnosis and Natural History of Multiple System Atrophy, Cerebellar Type. Cerebellum 15, 663–679 (2016). https://doi.org/10.1007/s12311-015-0728-y

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