Multiple System Atrophy

 

 Buy Article Permissions and Reprints

Abstract

Multiple system atrophy (MSA) is a rare adult-onset synucleinopathy associated with dysautonomia and the variable presence of poorly levodopa-responsive parkinsonism and/or cerebellar ataxia. Other clinical symptoms that can be associated with MSA include hyperreflexia, stridor, sleep apnea, and rapid eye movement sleep behavior disorder (RBD). Mean survival from time of diagnosis ranges between 6 to 10 years, and definitive diagnosis is made on autopsy with demonstration of oligodendroglial cytoplasmic inclusions consisting of fibrillar α-synuclein. Magnetic resonance imaging (MRI) may be positive for cruciform T2 hyperintensity within the pons (the “hot cross bun sign”), volume loss in the pons and cerebellum, and T2 signal loss in the dorsolateral putamen with hyperintense rim on fluid attenuated inversion recovery (FLAIR) sequencing. Although most cases are sporadic, genetic polymorphisms have been identified both in familial and sporadic cases of MSA, and influence observed phenotypes. Treatment is symptomatic, with both pharmacological and nonpharmacological strategies. There are currently no consensus guidelines on management. Current and future research is aimed at identifying biomarkers and developing disease-modifying therapies.

• References

• 1 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
  CrossrefPubMedGoogle Scholar
• 2 Gai WP, Power JH, Blumbergs PC, Blessing WW. Multiple-system atrophy: a new alpha-synuclein disease?. Lancet 1998; 352 (9127) 547-548
  CrossrefPubMedGoogle Scholar
• 3 Dickson DW, Lin W, Liu WK, Yen SH. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol 1999; 9 (4) 721-732
  CrossrefPubMedGoogle Scholar
• 4 Vanacore N. Epidemiological evidence on multiple system atrophy. J Neural Transm 2005; 112 (12) 1605-1612
  CrossrefPubMedGoogle Scholar
• 5 Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997; 49 (5) 1284-1288
  CrossrefPubMedGoogle Scholar
• 6 Bjornsdottir A, Gudmundsson G, Blondal H, Olafsson E. Incidence and prevalence of multiple system atrophy: a nationwide study in Iceland. J Neurol Neurosurg Psychiatry 2013; 84 (2) 136-140
  CrossrefPubMedGoogle Scholar
• 7 Schrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 1999; 354 (9192) 1771-1775
  CrossrefPubMedGoogle Scholar
• 8 Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009; 8 (12) 1172-1178
  CrossrefPubMedGoogle Scholar
• 9 Vanacore N, Bonifati V, Fabbrini G , et al; European Study Group on Atypical Parkinsonism (ESGAP); ESGAP Consortium. European Study Group on Atypical Parkinsonisms. Epidemiology of multiple system atrophy. Neurol Sci 2001; 22 (1) 97-99
  CrossrefPubMedGoogle Scholar
• 10 Vanacore N, Bonifati V, Fabbrini G , et al; European Study Group on Atypical Parkinsonisms. Smoking habits in multiple system atrophy and progressive supranuclear palsy. Neurology 2000; 54 (1) 114-119
  CrossrefPubMedGoogle Scholar
• 11 Vidal JS, Vidailhet M, Elbaz A, Derkinderen P, Tzourio C, Alpérovitch A. Risk factors of multiple system atrophy: a case-control study in French patients. Mov Disord 2008; 23 (6) 797-803
  CrossrefPubMedGoogle Scholar
• 12 Ito H, Kusaka H, Matsumoto S, Imai T. Striatal efferent involvement and its correlation to levodopa efficacy in patients with multiple system atrophy. Neurology 1996; 47 (5) 1291-1299
  CrossrefPubMedGoogle Scholar
• 13 Ozawa T, Paviour D, Quinn NP , et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 2004; 127 (Pt 12) 2657-2671
  CrossrefPubMedGoogle Scholar
• 14 Dusek P, Jankovic J, Le W. Iron dysregulation in movement disorders. Neurobiol Dis 2012; 46 (1) 1-18
  CrossrefPubMedGoogle Scholar
• 15 Visanji NP, Collingwood JF, Finnegan ME, Tandon A, House E, Hazrati LN. Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson's disease and multiple system atrophy. J Parkinsons Dis 2013; 3 (4) 523-537
  PubMedGoogle Scholar
• 16 Kawai Y, Suenaga M, Takeda A , et al. Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology 2008; 70 (16 Pt 2) 1390-1396
  CrossrefPubMedGoogle Scholar
• 17 Paviour DC, Price SL, Jahanshahi M, Lees AJ, Fox NC. Regional brain volumes distinguish PSP, MSA-P, and PD: MRI-based clinico-radiological correlations. Mov Disord 2006; 21 (7) 989-996
  CrossrefPubMedGoogle Scholar
• 18 Jellinger KA, Lantos PL. Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 2010; 119 (6) 657-667
  CrossrefPubMedGoogle Scholar
• 19 Papp MI, Lantos PL. The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain 1994; 117 (Pt 2) 235-243
  CrossrefPubMedGoogle Scholar
• 20 Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M. The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol 1997; 93 (6) 585-591
  CrossrefPubMedGoogle Scholar
• 21 Armstrong RA, Cairns NJ, Lantos PL. Multiple system atrophy (MSA): topographic distribution of the alpha-synuclein-associated pathological changes. Parkinsonism Relat Disord 2006; 12 (6) 356-362
  CrossrefPubMedGoogle Scholar
• 22 Stemberger S, Scholz SW, Singleton AB, Wenning GK. Genetic players in multiple system atrophy: unfolding the nature of the beast. Neurobiol Aging 2011; 32 (10) e5-e14
  PubMedGoogle Scholar
• 23 Kiely AP, Asi YT, Kara E , et al. α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy?. Acta Neuropathol 2013; 125 (5) 753-769
  CrossrefPubMedGoogle Scholar
• 24 Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H. Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes. Mov Disord 2008; 23 (8) 1161-1167
  CrossrefPubMedGoogle Scholar
• 25 Ubhi K, Rockenstein E, Kragh C , et al. Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96. Eur J Neurosci 2014; 39 (6) 1026-1041
  CrossrefPubMedGoogle Scholar
• 26 Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med 2013; 369 (3) 233-244
  CrossrefPubMedGoogle Scholar
• 27 Ozawa T. The COQ2 mutations in Japanese multiple system atrophy: impact on the pathogenesis and phenotypic variation. Mov Disord 2014; 29 (2) 184
  CrossrefPubMedGoogle Scholar
• 28 Ozawa T, Revesz T, Paviour D , et al. Difference in MSA phenotype distribution between populations: genetics or environment?. J Parkinsons Dis 2012; 2 (1) 7-18
  PubMedGoogle Scholar
• 29 Ozawa T, Tada M, Kakita A , et al. The phenotype spectrum of Japanese multiple system atrophy. J Neurol Neurosurg Psychiatry 2010; 81 (11) 1253-1255
  CrossrefPubMedGoogle Scholar
• 30 Gilman S, Wenning GK, Low PA , et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71 (9) 670-676
  CrossrefPubMedGoogle Scholar
• 31 Beck RO, Betts CD, Fowler CJ. Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases. J Urol 1994; 151 (5) 1336-1341
  PubMedGoogle Scholar
• 32 Köllensperger M, Geser F, Ndayisaba JP , et al; EMSA-SG. Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov Disord 2010; 25 (15) 2604-2612
  CrossrefPubMedGoogle Scholar
• 33 Wenning GK, Tison F, Seppi K , et al; Multiple System Atrophy Study Group. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19 (12) 1391-1402
  CrossrefPubMedGoogle Scholar
• 34 Wenning GK, Geser F, Krismer F , et al; European Multiple System Atrophy Study Group. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013; 12 (3) 264-274
  CrossrefPubMedGoogle Scholar
• 35 Okuma Y, Fujishima K, Miwa H, Mori H, Mizuno Y. Myoclonic tremulous movements in multiple system atrophy are a form of cortical myoclonus. Mov Disord 2005; 20 (4) 451-456
  CrossrefPubMedGoogle Scholar
• 36 Plazzi G, Corsini R, Provini F , et al. REM sleep behavior disorders in multiple system atrophy. Neurology 1997; 48 (4) 1094-1097
  CrossrefPubMedGoogle Scholar
• 37 Munschauer FE, Loh L, Bannister R, Newsom-Davis J. Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 1990; 40 (4) 677-679
  CrossrefPubMedGoogle Scholar
• 38 Merlo IM, Occhini A, Pacchetti C, Alfonsi E. Not paralysis, but dystonia causes stridor in multiple system atrophy. Neurology 2002; 58 (4) 649-652
  CrossrefPubMedGoogle Scholar
• 39 Boesch SM, Wenning GK, Ransmayr G, Poewe W. Dystonia in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 72 (3) 300-303
  CrossrefPubMedGoogle Scholar
• 40 Siri C, Duerr S, Canesi M , et al. A cross-sectional multicenter study of cognitive and behavioural features in multiple system atrophy patients of the parkinsonian and cerebellar type. J Neural Transm 2013; 120 (4) 613-618
  CrossrefPubMedGoogle Scholar
• 41 Jecmenica-Lukic M, Poewe W, Tolosa E, Wenning GK. Premotor signs and symptoms of multiple system atrophy. Lancet Neurol 2012; 11 (4) 361-368
  CrossrefPubMedGoogle Scholar
• 42 Schwarz J, Weis S, Kraft E , et al. Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 1996; 60 (1) 98-101
  CrossrefPubMedGoogle Scholar
• 43 Schocke MF, Seppi K, Esterhammer R , et al. Diffusion-weighted MRI differentiates the Parkinson variant of multiple system atrophy from PD. Neurology 2002; 58 (4) 575-580
  CrossrefPubMedGoogle Scholar
• 44 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 2014; 121 (5) 507-512
  CrossrefPubMedGoogle Scholar
• 45 Brooks DJ, Seppi K ; Neuroimaging Working Group on MSA. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 2009; 24 (7) 949-964
  CrossrefPubMedGoogle Scholar
• 46 Paviour DC, Williams D, Fowler CJ, Quinn NP, Lees AJ. Is sphincter electromyography a helpful investigation in the diagnosis of multiple system atrophy? A retrospective study with pathological diagnosis. Mov Disord 2005; 20 (11) 1425-1430
  CrossrefPubMedGoogle Scholar
• 47 Treglia G, Stefanelli A, Cason E, Cocciolillo F, Di Giuda D, Giordano A. Diagnostic performance of iodine-123-metaiodobenzylguanidine scintigraphy in differential diagnosis between Parkinson's disease and multiple-system atrophy: a systematic review and a meta-analysis. Clin Neurol Neurosurg 2011; 113 (10) 823-829
  CrossrefPubMedGoogle Scholar
• 48 Abdo WF, Bloem BR, Van Geel WJ, Esselink RA, Verbeek MM. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson's disease. Neurobiol Aging 2007; 28 (5) 742-747
  CrossrefPubMedGoogle Scholar
• 49 Herbert MK, Eeftens JM, Aerts MB , et al. CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls. Parkinsonism Relat Disord 2014; 20 (1) 112-115
  CrossrefPubMedGoogle Scholar
• 50 Wenning GK, Scherfler C, Granata R , et al. Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed parkinsonian syndromes: a clinicopathological study. J Neurol Neurosurg Psychiatry 1999; 67 (5) 620-623
  CrossrefPubMedGoogle Scholar
• 51 Kirchhof K, Apostolidis AN, Mathias CJ, Fowler CJ. Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study. Int J Impot Res 2003; 15 (4) 293-298
  CrossrefPubMedGoogle Scholar
• 52 O'Sullivan SS, Massey LA, Williams DR , et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 2008; 131 (Pt 5) 1362-1372
  PubMedGoogle Scholar
• 53 Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med 2013; 14 (8) 744-748
  CrossrefPubMedGoogle Scholar
• 54 Lalich IJ, Ekbom DC, Starkman SJ, Orbelo DM, Morgenthaler TI. Vocal fold motion impairment in multiple system atrophy. Laryngoscope 2014; 124 (3) 730-735
  CrossrefPubMedGoogle Scholar
• 55 Seppi K, Yekhlef F, Diem A , et al. Progression of parkinsonism in multiple system atrophy. J Neurol 2005; 252 (1) 91-96
  CrossrefPubMedGoogle Scholar
• 56 Flabeau O, Meissner WG, Tison F. Multiple system atrophy: current and future approaches to management. Ther Adv Neurol Disord 2010; 3 (4) 249-263
  CrossrefPubMedGoogle Scholar
• 57 Friess E, Kuempfel T, Modell S , et al. Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat Disord 2006; 12 (7) 432-437
  CrossrefPubMedGoogle Scholar
• 58 Wenning GK ; Working Group on Atypical Parkinsonism of the Austrian Parkinson's Society. Placebo-controlled trial of amantadine in multiple-system atrophy. Clin Neuropharmacol 2005; 28 (5) 225-227
  CrossrefPubMedGoogle Scholar
• 59 Holmberg B, Johansson JO, Poewe W , et al; Growth-Hormone MSA Study Group; European MSA Study Group. Safety and tolerability of growth hormone therapy in multiple system atrophy: a double-blind, placebo-controlled study. Mov Disord 2007; 22 (8) 1138-1144
  CrossrefPubMedGoogle Scholar
• 60 Jankovic J, Gilden JL, Hiner BC , et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993; 95 (1) 38-48
  CrossrefPubMedGoogle Scholar
• 61 Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA ; Midodrine Study Group. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. JAMA 1997; 277 (13) 1046-1051
  CrossrefPubMedGoogle Scholar
• 62 Wright RA, Kaufmann HC, Perera R , et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51 (1) 120-124
  CrossrefPubMedGoogle Scholar
• 63 Singer W, Sandroni P, Opfer-Gehrking TL , et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol 2006; 63 (4) 513-518
  CrossrefPubMedGoogle Scholar
• 64 Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71 (3) 371-374
  CrossrefPubMedGoogle Scholar
• 65 Ferini-Strambi L, Marelli S. Sleep dysfunction in multiple system atrophy. Curr Treat Options Neurol 2012; 14 (5) 464-473
  CrossrefPubMedGoogle Scholar
• 66 Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease. Lancet Neurol 2013; 12 (7) 716-726
  CrossrefPubMedGoogle Scholar
• 67 Ullman M, Vedam-Mai V, Resnick AS , et al. Deep brain stimulation response in pathologically confirmed cases of multiple system atrophy. Parkinsonism Relat Disord 2012; 18 (1) 86-88
  CrossrefPubMedGoogle Scholar
• 68 Acar F, Acar G, Bir LS, Gedik B, Oğuzhanoğlu A. Deep brain stimulation of the pedunculopontine nucleus in a patient with freezing of gait. Stereotact Funct Neurosurg 2011; 89 (4) 214-219
  CrossrefPubMedGoogle Scholar
• 69 Mathias CJ, Senard JM, Braune S , et al. L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res 2001; 11 (4) 235-242
  CrossrefPubMedGoogle Scholar
• 70 Wu SH, Yang HX, Jiang GH, Gong DR, Wang LX. Preliminary results of cord blood mononuclear cell therapy for multiple system atrophy: a report of three cases. Med Princ Pract 2013;
  PubMedGoogle Scholar
• 71 Novak P, Williams A, Ravin P, Zurkiya O, Abduljalil A, Novak V. Treatment of multiple system atrophy using intravenous immunoglobulin. BMC Neurol 2012; 12: 131
  CrossrefPubMedGoogle Scholar
• 72 Saccà F, Marsili A, Quarantelli M , et al. A randomized clinical trial of lithium in multiple system atrophy. J Neurol 2013; 260 (2) 458-461
  CrossrefPubMedGoogle Scholar
• 73 Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN ; NNIPPS Study Group. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain 2009; 132 (Pt 1) 156-171
  PubMedGoogle Scholar
• 74 Low PA, Robertson D, Gilman S , et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13 (3) 268-275
  CrossrefPubMedGoogle Scholar
• 75 Poewe W, Barone P, Gliadi N , et al. A randomized, placebo-controlled clinical trial to assess the effects of rasagiline in patients with multiple system atrophy of the parkinsonian subtype. Abstract presented at the 16th International Congress of Parkinson's Disease and Movement Disorders; June 17–21, 2012; Dublin, Ireland
  PubMedGoogle Scholar
• 76 Dodel R, Spottke A, Gerhard A , et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 2010; 25 (1) 97-107
  CrossrefPubMedGoogle Scholar