Multiple system atrophy

MSA is characterized by the following: Autonomic and at least one Motor (clinically established MSA criteria 2022){{cite journal | vauthors = Swan L, Dupont J | title = Multiple system atrophy | journal = Physical Therapy | volume = 79 | issue = 5 | pages = 488–494 | date = May 1999 | pmid = 10331752 | doi = 10.1093/ptj/79.5.488 | doi-access = free }}{{cite journal | vauthors = Burn DJ, Jaros E | title = Multiple system atrophy: cellular and molecular pathology | journal = Molecular Pathology | volume = 54 | issue = 6 | pages = 419–426 | date = December 2001 | pmid = 11724918 | pmc = 1187133 }}

• autonomic dysfunction: Post-void urinary residual volume ≥100 mL (usually by ultrasound); Unexplained urinary urge incontinence; or Neurogenic orthostatic hypotension (≥20/10 mmHg blood pressure drop) within 3 minutes (usually by head‐up tilt)
• parkinsonism (muscle rigidity +/ tremor and slow movement: MSA-P)
• cerebellar ataxia (Poor coordination/unsteady walking: MSA-C)

A variant with combined features of MSA and dementia with Lewy bodies may also exist.{{MEDRS|date=March 2018}}{{MEDRS|date=March 2018}}{{cite journal | vauthors = Sikorska B, Papierz W, Preusser M, Liberski PP, Budka H | title = Synucleinopathy with features of both multiple system atrophy and dementia with Lewy bodies | journal = Neuropathology and Applied Neurobiology | volume = 33 | issue = 1 | pages = 126–129 | date = February 2007 | pmid = 17239015 | doi = 10.1111/j.1365-2990.2006.00817.x | s2cid = 40186391 }} There have also been occasional instances of frontotemporal lobar degeneration associated with MSA.{{cite journal | vauthors = Aoki N, Boyer PJ, Lund C, Lin WL, Koga S, Ross OA, Weiner M, Lipton A, Powers JM, White CL, Dickson DW | display-authors = 6 | title = Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein | journal = Acta Neuropathologica | volume = 130 | issue = 1 | pages = 93–105 | date = July 2015 | pmid = 25962793 | pmc = 6764097 | doi = 10.1007/s00401-015-1442-z }}

The most common first sign of MSA is the appearance of an "akinetic-rigid syndrome" (i.e. slowness of initiation of movement resembling Parkinson's disease) found in 62% at first presentation. Other common signs at onset include problems with balance (cerebellar ataxia) found in 22% at first presentation, followed by genito-urinary symptoms (9%): both men and women often experience urgency, frequency, incomplete bladder emptying, or an inability to pass urine (retention). About 1 in 5 MSA patients experience a fall in their first year of disease.{{cite journal | vauthors = Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN | title = Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study | journal = Brain | volume = 132 | issue = Pt 1 | pages = 156–171 | date = January 2009 | pmid = 19029129 | pmc = 2638696 | doi = 10.1093/brain/awn291 }}

For men, the first sign can be erectile dysfunction. Women have also reported reduced genital sensitivity.{{cite journal | vauthors = Oertel WH, Wächter T, Quinn NP, Ulm G, Brandstädter D | title = Reduced genital sensitivity in female patients with multiple system atrophy of parkinsonian type | journal = Movement Disorders | volume = 18 | issue = 4 | pages = 430–432 | date = April 2003 | pmid = 12671951 | doi = 10.1002/mds.10384 | s2cid = 28102026 }}

As the disease progresses, one of three groups of symptoms predominates.

These are:{{Cite journal |last=Stępnicki |date=2018-08-20 |title=Current Concepts and Treatments of Schizophrenia |journal=Molecules |volume=23 |issue=8 |pages=2087 |doi=10.3390/molecules23082087 |doi-access= free|issn=1420-3049 |pmc=6222385 |pmid=30127324}}

1. Parkinsonism - slow, stiff movement, writing becomes small and spidery{{cite book |vauthors=Aminoff MJ, Greenberg DA, Simon RP | title = Clinical Neurology | publisher = Lange: McGraw-Hill Medical | edition = 6th | pages = 241–45 |year = 2005 | isbn = 978-0-07-142360-1 |chapter= Chapter 7: Movement disorders}}{{cite journal | vauthors = Ogawa T, Fujii S, Kuya K, Kitao SI, Shinohara Y, Ishibashi M, Tanabe Y | title = Role of Neuroimaging on Differentiation of Parkinson's Disease and Its Related Diseases | journal = Yonago Acta Medica | volume = 61 | issue = 3 | pages = 145–155 | date = September 2018 | pmid = 30275744 | pmc = 6158357 | doi = 10.33160/yam.2018.09.001 | type = Review | quote = Parkinsonian syndromes are a group of movement disorders characterized by classical motor symptoms such as tremors, bradykinesia, and rigidity. They are most frequently due to primary neurodegenerative disease, resulting in the loss of dopaminergic nerve terminals along the nigrostriatal pathway, similar to idiopathic PD, MSA, PSP, CBD, and DLB. }}
2. Cerebellar dysfunction - difficulty coordinating movement and balance{{cite book | vauthors = Hodos W |chapter= Evolution of Cerebellum|title=Encyclopedia of Neuroscience|publisher=Springer|date=2009|pages=1240–1243|doi=10.1007/978-3-540-29678-2_3124|isbn=978-3-540-23735-8}}
3. Autonomic nervous system dysfunction - impaired automatic body functions, including one, some, or all of the following:{{DorlandsDict|nine/000950637|Autonomic nervous system}}

::* postural or orthostatic hypotension, resulting in dizziness or fainting upon standing up{{cite web |url=https://www.lecturio.com/concepts/hypotension/| title=Hypotension|website=The Lecturio Medical Concept Library |access-date= 27 July 2021}}

::* urinary incontinence or urinary retention{{cite book | vauthors = Ackley B | title = Nursing diagnosis handbook : an evidence-based guide to planning care |edition=9th| publisher = Mosby | location = Maryland Heights, Mo | year = 2010 | isbn = 9780323071505 }}{{cite journal| vauthors = Richard C, Amarenco G, Palma JA, Kaufmann H, Drapier S, Gamé X, Brucker B, Peyronnet B | title = Early bladder dysfunction in multiple system atrophy: who seek shall find | journal = Clin Auton Res | date = 2019 | volume = 29 | issue = 6 | pages = 625–6 | pmid = 1705345 | doi = 10.1007/s10286-019-00648-2 }}{{cite journal| vauthors = Sakakibara R, Panicker J, Finazzi-Agro E, Iacovelli V, Bruschini H, Subcomittee PD,NUPC,ICS | title = A guideline for the management of bladder dysfunction in Parkinson's disease and other gait disorders | journal = Neurourol Urodyn | date = 2016 | volume = 35 | issue = 5 | pages = 551–63 | pmid = 25810035 | doi = 10.1002/nau.22764 }}

::* impotence{{cite book | vauthors = Cunningham GR, Rosen RC | chapter = Overview of male sexual dysfunction. | title = UpToDate | veditors = Martin KA | publisher = UpToDate | location = Waltham, MA | date = 2018 }}

::* constipation{{cite web |url=https://www.lecturio.com/concepts/constipation/| title=Constipation|website=The Lecturio Medical Concept Library |access-date= 27 July 2021}}

::* vocal cord paralysis

::* dry mouth and skin

::* trouble regulating body temperature due to sweating deficiency in all parts of the body

::* loud snoring, abnormal breathing or inspiratory stridor during sleep

::* other sleep disorders including sleep apnea, REM behavior disorder{{cite journal | vauthors = Gilman S, Koeppe RA, Chervin RD, Consens FB, Little R, An H, Junck L, Heumann M | display-authors = 6 | title = REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA | journal = Neurology | volume = 61 | issue = 1 | pages = 29–34 | date = July 2003 | pmid = 12847152 | doi = 10.1212/01.wnl.0000073745.68744.94 | s2cid = 9538306 }}

::* double vision{{cite web |url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Multiple-System-Atrophy |title=What is multiple system atrophy? |author= |website=NIH |access-date=November 25, 2018 }}

::*muscle twitches

::* Cognitive impairment{{cite journal|author3-link=Bernhard Landwehrmeyer | vauthors = Brown RG, Lacomblez L, Landwehrmeyer BG, Bak T, Uttner I, Dubois B, Agid Y, Ludolph A, Bensimon G, Payan C, Leigh NP | display-authors = 6 | title = Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy | journal = Brain | volume = 133 | issue = Pt 8 | pages = 2382–2393 | date = August 2010 | pmid = 20576697 | doi = 10.1093/brain/awq158 | doi-access = free }}

One study found a correlation between the deletion of genes in a specific genetic region and the development of MSA in a group of Japanese patients. The region in question includes the SHC2 gene which, in mice and rats, appears to have some function in the nervous system. The authors of this study hypothesized that there may be a link between the deletion of the SHC2 and the development of MSA.{{cite journal | vauthors = Sasaki H, Emi M, Iijima H, Ito N, Sato H, Yabe I, Kato T, Utsumi J, Matsubara K | display-authors = 6 | title = Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy | journal = Molecular Brain | volume = 4 | pages = 24 | date = June 2011 | pmid = 21658278 | pmc = 3141657 | doi = 10.1186/1756-6606-4-24 | quote = Copy number loss of SHC2 strongly indicates a causal link to MSA. | doi-access = free }}

A follow-up study was unable to replicate this finding in American MSA patients.{{cite journal | vauthors = Ferguson MC, Garland EM, Hedges L, Womack-Nunley B, Hamid R, Phillips JA, Shibao CA, Raj SR, Biaggioni I, Robertson D | display-authors = 6 | title = SHC2 gene copy number in multiple system atrophy (MSA) | journal = Clinical Autonomic Research | volume = 24 | issue = 1 | pages = 25–30 | date = February 2014 | pmid = 24170347 | pmc = 3946192 | doi = 10.1007/s10286-013-0216-8 }} The authors of the study concluded that "Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population. This is in contrast to the Japanese experience reported by Sasaki et al., likely reflecting heterogeneity of the disease in different genetic backgrounds."{{clarify|date=July 2021}}

Another study investigated the frequency of RFC1 intronic repeat expansions, a phenomenon implicated in CANVAS; a disease with a diagnostic overlap with MSA.{{cite journal | vauthors = Sullivan R, Yau WY, Chelban V, Rossi S, O'Connor E, Wood NW, Cortese A, Houlden H | display-authors = 6 | title = RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy | journal = Movement Disorders | volume = 35 | issue = 7 | pages = 1277–1279 | date = July 2020 | pmid = 32333430 | doi = 10.1002/mds.28074 | s2cid = 216129457 }}{{cite journal | vauthors = Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H | display-authors = 6 | title = Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia | journal = Nature Genetics | volume = 51 | issue = 4 | pages = 649–658 | date = April 2019 | pmid = 30926972 | pmc = 6709527 | doi = 10.1038/s41588-019-0372-4 }} The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause.

Multiple system atrophy can be explained as cell loss and gliosis or a proliferation of astrocytes in damaged areas of the central nervous system. This damage forms a scar which is then termed a glial scar. The presence of inclusion bodies known as Papp–Lantos bodies, in the movement, balance, and autonomic-control centres of the brain are the defining histopathologic hallmark of MSA.{{cite journal | vauthors = Jellinger KA, Lantos PL | title = Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update | journal = Acta Neuropathologica | volume = 119 | issue = 6 | pages = 657–667 | date = June 2010 | pmid = 20309568 | doi = 10.1007/s00401-010-0672-3 | s2cid = 19759468 }}

The major filamentous component of Papp-Lantos bodies, glial and neuronal cytoplasmic inclusions, is alpha-synuclein.{{cite journal | vauthors = Arima K, Uéda K, Sunohara N, Arakawa K, Hirai S, Nakamura M, Tonozuka-Uehara H, Kawai M | display-authors = 6 | title = NACP/alpha-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy | journal = Acta Neuropathologica | volume = 96 | issue = 5 | pages = 439–444 | date = November 1998 | pmid = 9829806 | doi = 10.1007/s004010050917 | s2cid = 10804119 }} Mutations in this substance may play a role in the disease.{{cite journal | vauthors = Al-Chalabi A, Dürr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, Leigh PN, Bensimon G | display-authors = 6 | title = Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy | journal = PLOS ONE | volume = 4 | issue = 9 | pages = e7114 | date = September 2009 | pmid = 19771175 | pmc = 2743996 | doi = 10.1371/journal.pone.0007114 | doi-access = free | bibcode = 2009PLoSO...4.7114A }} The conformation of the alpha-synuclein is different from that of alpha-synuclein in Lewy bodies.{{cite journal | vauthors = Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL, Zhang B, Pitkin RM, Olufemi MF, Luk KC, Trojanowski JQ, Lee VM | display-authors = 6 | title = Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies | journal = Nature | volume = 557 | issue = 7706 | pages = 558–563 | date = May 2018 | pmid = 29743672 | pmc = 5970994 | doi = 10.1038/s41586-018-0104-4 | bibcode = 2018Natur.557..558P }} The disease probably starts with an oligodendrogliopathy.{{cite journal | vauthors = Stefanova N, Wenning GK | title = Review: Multiple system atrophy: emerging targets for interventional therapies | journal = Neuropathology and Applied Neurobiology | volume = 42 | issue = 1 | pages = 20–32 | date = February 2016 | pmid = 26785838 | pmc = 4788141 | doi = 10.1111/nan.12304 }} It has been proposed that the α-synuclein inclusions found in Oligodendrocytes result from the pruning and the engulfment of diseased axonal segments containing aggregated α-synuclein, i.e., of Lewy neurites {{cite journal | vauthors = De Nuccio F, Kashyrina M, Serinelli F, Laferrière F, Lofrumento DD, De Giorgi F, Ichas F | title = Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy? | journal = Biomolecules | volume = 13 | issue = 2 | pages = 269 | date = February 2023 | pmid = 36830639 | pmc = 9953613 | doi = 10.3390/biom13020269 | doi-access = free }}

Tau proteins have been found in some glial cytoplasmic inclusion bodies.{{cite journal | vauthors = Piao YS, Hayashi S, Hasegawa M, Wakabayashi K, Yamada M, Yoshimoto M, Ishikawa A, Iwatsubo T, Takahashi H | display-authors = 6 | title = Co-localization of alpha-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration | journal = Acta Neuropathologica | volume = 101 | issue = 3 | pages = 285–293 | date = March 2001 | pmid = 11307630 | doi = 10.1007/s004010000292 | s2cid = 25650403 }}

Clinical diagnostic criteria were defined in 1998{{cite journal | vauthors = Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK | display-authors = 6 | title = Consensus statement on the diagnosis of multiple system atrophy | journal = Journal of the Neurological Sciences | volume = 163 | issue = 1 | pages = 94–98 | date = February 1999 | pmid = 10223419 | doi = 10.1016/s0022-510x(98)00304-9 | hdl-access = free | s2cid = 13307970 | hdl = 2027.42/41757 }} and updated in 2007 and in 2022.{{cite journal| vauthors = Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, Palma JA, Meissner WG, Krismer F, Berg D, Cortelli P, Freeman R, Halliday G, Höglinger G, Lang A, Ling H, Litvan I, Low P, Miki Y, Panicker J, Pellecchia MT, Quinn N, Sakakibara R, Stamelou M, Tolosa E, Tsuji S, Warner T, Poewe W, Kaufmann H | title = The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy | journal = Movement Disorders | date = 2022 | volume = 37 | issue = 6 | pages = 1131–48 | pmid = 35445419 | doi = 10.1002/mds.29005 | pmc = 9321158 | hdl = 11585/899814 | hdl-access = free }} Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.{{cite web |url= http://www.mc.vanderbilt.edu/root/vumc.php?site=adc&doc=4791 | work = Vanderbilt Autonomic Dysfunction Center |title=Multiple System Atrophy / Shy Drager Syndrome |access-date = May 29, 2010 }}{{cite journal | vauthors = Bloomfield SM, Hanna PA, Noor ER, Dalvi AI |date=2018-09-24 | veditors = Benbadis SR | url=http://emedicine.medscape.com/article/1154074-overview#a2|title=multiple system atrophy overview | journal = Medscape | publisher = WebMD LLC }}{{cite journal | vauthors = Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW | display-authors = 6 | title = When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients | journal = Neurology | volume = 85 | issue = 5 | pages = 404–412 | date = August 2015 | pmid = 26138942 | pmc = 4534078 | doi = 10.1212/WNL.0000000000001807 }}

Features characteristic of OPCA include progressive cerebellar ataxia, leading to clumsiness in body movements, veering from midline when walking, wide-based stance, and falls without signs of paralysis or weakness.{{cite journal|last=Landers|first=M|author2=Adams M |author3=Acosta K |author4=Fox A. |title=Challenge-oriented gait and balance training in sporadic olivopontocerebellar atrophy: a case study.|journal=J Neurol Phys Ther|year=2009|volume=33|issue=3|pages=160–168|doi=10.1097/npt.0b013e3181b511f4|pmid=19809395|s2cid=24642594|doi-access=free}}{{cite journal|last=Berciano|first=J|author2=Boesch S |author3=Pérez-Ramos JM |author4=Wenning GK |title=Olivopontocerebellar atrophy: toward a better nosological definition.|journal=Mov. Disord.|year=2006|volume=21|issue=10|pages=1607–13|doi=10.1002/mds.21052|pmid=16874757|s2cid=38376147}} Clinical presentation can vary greatly between patients, but mostly affects speech, balance and walking.{{Cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001765/ |title=Olivopontocerebellar atrophy - PubMed Health |access-date=2017-09-07 |archive-date=2012-11-17 |archive-url=https://web.archive.org/web/20121117071439/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001765/ |url-status=dead }} Other possible neurological problems include spasmodic dysphonia, hypertonia, hyperreflexia, rigidity, dysarthria, dysphagia and neck dystonic posture. Diagnosis may be based on a thorough medical exam; the presence of signs and symptoms; imaging studies; various laboratory tests; and an evaluation of the family history.{{Cite web|url=https://rarediseases.info.nih.gov/diseases/7250/olivopontocerebellar-atrophy|title = Olivopontocerebellar atrophy | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program}}

File:Hot cross bun sign.jpg

Both MRI and CT scanning may show a decrease in the size of the cerebellum and pons in those with cerebellar features (MSA-C). The putamen is hypointense on T2-weighted MRI and may show an increased deposition of iron in the Parkinsonian (MSA-P) form. In MSA-C, a "hot cross bun" sign is sometimes found; it reflects atrophy of the pontocerebellar tracts that give T2 hyper intense signal intensity in the atrophic pons.

MRI changes are not required to diagnose the disease as these features are often absent, especially early in the course of the disease. Additionally, the changes can be quite subtle and are usually missed by examiners who are not experienced with MSA.{{citation needed|date=December 2020}}

Pathological diagnosis can only be made at autopsy by finding abundant glial cytoplasmic inclusions (GCIs) on histological specimens of the central nervous system.{{cite journal | vauthors = Papp MI, Kahn JE, Lantos PL | title = Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome) | journal = Journal of the Neurological Sciences | volume = 94 | issue = 1–3 | pages = 79–100 | date = December 1989 | pmid = 2559165 | doi = 10.1016/0022-510X(89)90219-0 | s2cid = 1199951 }}

Olivopontocerebellar atrophy can be used as a pathological term to describe degeneration of neurons in specific areas of the brain – the cerebellum, pons, and inferior olivary nucleus.{{cite web |title=NINDS Olivopontocerebellar Atrophy Information Page |access-date=7 Feb 2012 |url=http://www.ninds.nih.gov/disorders/opca/opca.htm |url-status=dead |archive-url=https://web.archive.org/web/20120127104017/http://www.ninds.nih.gov/disorders/opca/opca.htm |archive-date=2012-01-27 }} OPCA is present in several neurodegenerative syndromes, including inherited and non-inherited forms of ataxia (such as the hereditary spinocerebellar ataxia known as Machado–Joseph disease) and MSA, with which it is primarily associated.

Contrary to most other synucleinopathies, which develop α-synuclein inclusions primarily in neuronal cell populations,{{cite journal | vauthors = Waxman EA, Giasson BI | title = Molecular mechanisms of alpha-synuclein neurodegeneration | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1792 | issue = 7 | pages = 616–624 | date = July 2009 | pmid = 18955133 | pmc = 2756732 | doi = 10.1016/j.bbadis.2008.09.013 }} MSA presents with extensive pathological α-synuclein inclusions in the cytosol of oligodendrocytes (glial cytoplasmic inclusions), with limited pathology in neurons.{{cite journal | vauthors = Burn DJ, Jaros E | title = Multiple system atrophy: cellular and molecular pathology | journal = Molecular Pathology | volume = 54 | issue = 6 | pages = 419–426 | date = December 2001 | pmid = 11724918 | pmc = 1187133 }} MSA also differs from other synucleinopathies in its regional pathological presentation, with α-synuclein positive inclusions detected predominantly in the striatum, midbrain, pons, medulla and cerebellum,{{cite journal | vauthors = Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL, Revesz T | display-authors = 6 | title = The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations | journal = Brain | volume = 127 | issue = Pt 12 | pages = 2657–2671 | date = December 2004 | pmid = 15509623 | doi = 10.1093/brain/awh303 | doi-access = free }}{{cite journal | vauthors = Brettschneider J, Suh E, Robinson JL, Fang L, Lee EB, Irwin DJ, Grossman M, Van Deerlin VM, Lee VM, Trojanowski JQ | display-authors = 6 | title = Converging Patterns of α-Synuclein Pathology in Multiple System Atrophy | journal = Journal of Neuropathology and Experimental Neurology | volume = 77 | issue = 11 | pages = 1005–1016 | date = November 2018 | pmid = 30203094 | pmc = 6181179 | doi = 10.1093/jnen/nly080 | doi-access = free }} rather than the brainstem, limbic and cortical regions typically effected in Lewy inclusion diseases. However, recent studies using novel, monoclonal antibodies specific for C-terminally truncated α-synuclein (αSynΔC) have now shown that neuronal α-synuclein pathology is more abundant than previously thought.{{cite journal | vauthors = Hass EW, Sorrentino ZA, Lloyd GM, McFarland NR, Prokop S, Giasson BI | title = Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy | journal = Acta Neuropathologica Communications | volume = 9 | issue = 1 | pages = 80 | date = May 2021 | pmid = 33941284 | pmc = 8091528 | doi = 10.1186/s40478-021-01173-y | doi-access = free }}{{cite journal | vauthors = Hass EW, Sorrentino ZA, Xia Y, Lloyd GM, Trojanowski JQ, Prokop S, Giasson BI | title = Disease-, region- and cell type specific diversity of α-synuclein carboxy terminal truncations in synucleinopathies | journal = Acta Neuropathologica Communications | volume = 9 | issue = 1 | pages = 146 | date = August 2021 | pmid = 34454615 | pmc = 8403399 | doi = 10.1186/s40478-021-01242-2 | doi-access = free }} One group revealed robust α-synuclein pathology in the pontine nuclei and medullary inferior olivary nucleus upon histological analysis of neurological tissue from MSA patients.

Histopathological investigation on six cases of pathologically confirmed MSA, using antibodies directed at a variety of α-synuclein epitopes, revealed substantial variation in α-synuclein protein deposition across both cases and brain regions within cases, providing evidence for 'strains' of aggregated conformers that may differentially promote pathological prion-like spread.{{cite journal | vauthors = Dhillon JS, Trejo-Lopez JA, Riffe C, McFarland NR, Hiser WM, Giasson BI, Yachnis AT | title = Dissecting α-synuclein inclusion pathology diversity in multiple system atrophy: implications for the prion-like transmission hypothesis | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 99 | issue = 7 | pages = 982–992 | date = July 2019 | pmid = 30737468 | pmc = 7209695 | doi = 10.1038/s41374-019-0198-9 | doi-access = free }}

In 2020, researchers at The University of Texas Health Science Center at Houston concluded that protein misfolding cyclic amplification could be used to distinguish between two progressive neurodegenerative diseases, Parkinson's disease and multiple system atrophy, being the first process to give an objective diagnosis of Multiple System Atrophy instead of just a differential diagnosis.{{cite news |title=Method Can Distinguish Parkinson's Disease From multiple system atrophy |url=https://www.technologynetworks.com/diagnostics/news/method-can-distinguish-parkinsons-disease-from-multiple-system-atrophy-330385 |access-date=23 February 2020 |work=Diagnostics from Technology Networks |language=en}}{{cite journal | vauthors = Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, Hu B, Schmeichel A, Singer W, Wu G, Tsai AL, Shirani H, Nilsson KP, Low PA, Soto C | display-authors = 6 | title = Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy | journal = Nature | volume = 578 | issue = 7794 | pages = 273–277 | date = February 2020 | pmid = 32025029 | pmc = 7066875 | doi = 10.1038/s41586-020-1984-7 | bibcode = 2020Natur.578..273S }}

MSA is one of several neurodegenerative diseases known as synucleinopathies: they have in common an abnormal accumulation of alpha-synuclein protein in various parts of the brain. Other synucleinopathies include Parkinson's disease, the Lewy body dementias, and other more rare conditions.{{cite journal | vauthors = Goedert M, Jakes R, Spillantini MG | title = The Synucleinopathies: Twenty Years On | journal = Journal of Parkinson's Disease | volume = 7 | issue = s1 | pages = S51–S69 | date = 2017 | pmid = 28282814 | pmc = 5345650 | doi = 10.3233/JPD-179005 | type = Review }}

{{Infobox medical condition (new)

| name = Olivopontocerebellar atrophy

| image = Gray707.png

| caption = Sagittal section through right cerebellar hemisphere. The right olive has also been cut sagittally.

| field = Neurology

| synonyms = Multiple system atrophy – cerebellar subtype{{cite web |title=Multiple system atrophy – cerebellar subtype: MedlinePlus Medical Encyclopedia |url=https://medlineplus.gov/ency/article/000758.htm |website=medlineplus.gov |access-date=24 May 2019 |language=en}}

}}

Historically, many terms were used to refer to this disorder, based on the predominant systems presented. These terms were discontinued by consensus in 1996 and replaced with MSA and its subtypes,{{cite journal | author = The Consensus Committee of the American Autonomic Society and the American Academy of Neurology | title = Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. | journal = Neurology | volume = 46 | issue = 5 | pages = 1470 | date = May 1996 | pmid = 8628505 | doi = 10.1212/wnl.46.5.1470 | s2cid = 219212717 }} but awareness of these older terms and their definitions is helpful to understanding the relevant literature prior to 1996. These include striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy–Drager syndrome.{{cite journal | vauthors = Ahmed Z, Asi YT, Sailer A, Lees AJ, Houlden H, Revesz T, Holton JL | title = The neuropathology, pathophysiology and genetics of multiple system atrophy | journal = Neuropathology and Applied Neurobiology | volume = 38 | issue = 1 | pages = 4–24 | date = February 2012 | pmid = 22074330 | doi = 10.1111/j.1365-2990.2011.01234.x | s2cid = 22901422 }} A table describing the characteristics and modern names of these conditions follows:

The term olivopontocerebellar atrophy was originally coined by Joseph Jules Dejerine and André Thomas.{{WhoNamedIt|synd|1903}} - "Dejerine-Thomas atrophy"J. J. Dejerine, A. Thomas. L’atrophie olivo-ponto-cérébelleuse. Nouvelle iconographie de la Salpêtrière, Paris, 1900, 13: 330-370. 1912, 25: 223-250. It was subdivided as:

Non-hereditary diseases formerly categorized as olivopontocerebellar atrophy have were reclassified as forms of MSA[https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=mesh&cmd=search&term=multiple+system+atrophy MeSH Result] as well as to four hereditary types, that have been currently reclassified as four different forms of spinocerebellar ataxia:

The current terminology and diagnostic criteria for the disease were established at a 2007 conference of experts and set forth in a position paper.{{cite journal | vauthors = 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 | display-authors = 6 | title = Second consensus statement on the diagnosis of multiple system atrophy | journal = Neurology | volume = 71 | issue = 9 | pages = 670–676 | date = August 2008 | pmid = 18725592 | pmc = 2676993 | doi = 10.1212/01.wnl.0000324625.00404.15 }} This Second Consensus Statement defines two categories of MSA, based on the predominant symptoms of the disease at the time of evaluation. These are:

• MSA with predominant parkinsonism (MSA-P) - defined as MSA where extrapyramidal features predominate. It is sometimes termed striatonigral degeneration, a parkinsonian variant.{{citation needed|date=December 2020}}
• MSA with cerebellar features (MSA-C) - defined as MSA in which cerebellar ataxia predominates. It is sometimes termed sporadic olivopontocerebellar atrophy.{{citation needed|date=December 2020}}

Ongoing care from a neurologist specializing in movement disorders is recommended,{{by whom|date=March 2014}} because the complex symptoms of MSA are often not familiar to less-specialized neurologists. Hospice/homecare services can be very useful as disability progresses.{{citation needed|date=December 2020}}

Levodopa (L-Dopa), a drug used in the treatment of Parkinson's disease, improves parkinsonian symptoms in a small percentage of MSA patients. A recent trial reported that only 1.5% of MSA patients experienced any improvement at all when taking levodopa, their improvement was less than 50%, and even that improvement was a transient effect lasting less than one year. Poor response to L-Dopa has been suggested as a possible element in the differential diagnosis of MSA from Parkinson's disease.{{cite journal | vauthors = Calandra-Buonaura G, Doria A, Lopane G, Guaraldi P, Capellari S, Martinelli P, Cortelli P, Contin M | display-authors = 6 | title = Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease | journal = Journal of Neurology | volume = 263 | issue = 2 | pages = 250–256 | date = February 2016 | pmid = 26566913 | doi = 10.1007/s00415-015-7961-7 | s2cid = 189866517 }}

The drug riluzole is ineffective in treating MSA or PSP.

Management by rehabilitation professionals including physiatrists, physiotherapists, occupational therapists, speech therapists, and others for difficulties with walking/movement, daily tasks, and speech problems is essential.{{citation needed|date=December 2020}}

Physiotherapists can help to maintain the patient's mobility and will help to prevent contractures.{{cite journal | vauthors = Wenning GK, Colosimo C, Geser F, Poewe W | title = Multiple system atrophy | journal = The Lancet. Neurology | volume = 3 | issue = 2 | pages = 93–103 | date = February 2004 | pmid = 14747001 | doi = 10.1016/S1474-4422(03)00662-8 | s2cid = 10162139 }}
{{cite journal |vauthors=Wenning GK, Colosimo C, Geser F, Poewe W |title=Erratum |journal=Lancet Neurol |volume=3 |issue=3 |pages=137 |date=March 2004 |doi=10.1016/S1474-4422(04)00695-7 |s2cid=208782339 }} Instructing patients in gait training will help to improve their mobility and decrease their risk of falls.{{cite journal | vauthors = Hardy J | title = Multiple system atrophy: pathophysiology, treatment and nursing care | journal = Nursing Standard | volume = 22 | issue = 22 | pages = 50–6; quiz 58 | date = 2008 | pmid = 18333558 | doi = 10.7748/ns2008.02.22.22.50.c6359 }} A physiotherapist may also prescribe mobility aids such as a cane or a walker to increase the patient's safety.

Speech therapists may assist in assessing, treating and supporting speech (dysarthria) and swallowing difficulties (dysphagia). Speech changes mean that alternative communication may be needed, for example, communication aids or word charts.{{citation needed|date=December 2020}}

Early intervention of swallowing difficulties is particularly useful to allow for discussion around tube feeding further in the disease progression.{{citation needed|date=May 2018}} At some point in the progression of the disease, fluid and food modification may be implemented.{{citation needed|date=December 2020}}

One particularly serious problem, the drop in blood pressure upon standing up (with risk of fainting and thus injury from falling), often responds to fludrocortisone, a synthetic mineralocorticoid.{{cite journal | vauthors = Palma JA, Kaufmann H | title = Management of Orthostatic Hypotension | language = en-US | journal = Continuum | volume = 26 | issue = 1 | pages = 154–177 | date = February 2020 | pmid = 31996627 | pmc = 7339914 | doi = 10.1212/CON.0000000000000816 }} Another common drug treatment is the alpha-agonist midodrine.[https://www.mayoclinic.org/diseases-conditions/multiple-system-atrophy/symptoms-causes/syc-20356153 Multiple system atrophy (MSA)] mayoclinic.org, accessed 20 May 2018

Non-drug treatments include "head-up tilt" (elevating the head of the whole bed by about 10 degrees), salt tablets or increasing salt in the diet, generous intake of fluids, and pressure (elastic) stockings. Avoidance of triggers of low blood pressure, such as hot weather, alcohol, and dehydration, are crucial. The patient can be taught to move and transfer from sitting to standing slowly to decrease risk of falls and limit the effect of postural hypotension. Instruction in ankle pumping helps to return blood in the legs to the systemic circulation. Other preventative measures are raising the head of the bed by 8 in (20.3 cm), and the use of compression stockings and abdominal binders.

In addition to orthostatic hypotension, supine hypertension, where the BP is excessively high lying down, is a frequent problem in multiple system atrophy. Treatment of one symptom can easily aggravate the other, and supine hypertension in such patients has been linked to the same cardiovascular complications as essential hypertension.{{Cite journal |last1=Palma |first1=Jose-Alberto |last2=Redel-Traub |first2=Gabriel |last3=Porciuncula |first3=Angelo |last4=Samaniego-Toro |first4=Daniela |last5=Millar Vernetti |first5=Patricio |last6=Lui |first6=Yvonne W. |last7=Norcliffe-Kaufmann |first7=Lucy |last8=Kaufmann |first8=Horacio |date=June 2020 |title=The impact of supine hypertension on target organ damage and survival in patients with synucleinopathies and neurogenic orthostatic hypotension |journal=Parkinsonism & Related Disorders |language=en |volume=75 |issue=75 |pages=97–104 |doi=10.1016/j.parkreldis.2020.04.011 |pmc=7415666 |pmid=32516630}}

Social workers and occupational therapists can also help with coping with disability through the provision of equipment and home adaptations, services for caregivers and access to healthcare services, both for the person with MSA as well as family caregivers.{{citation needed|date=September 2020}}

The average lifespan after the onset of symptoms in patients with MSA is 6–10 years. Approximately 60% of patients require a wheelchair within five years of onset of the motor symptoms, and few patients survive beyond 12 years. The disease progresses without remission at a variable rate. Those who present at an older age, those with parkinsonian features, and those with severe autonomic dysfunction have a poorer prognosis. Those with predominantly cerebellar features and those who display autonomic dysfunction later have a better prognosis.

The most common causes of death are sudden death and death caused by infections, which include urinary catheterization infections, feeding tube infections, and aspiration pneumonia. Some deaths are caused by cachexia, also known as wasting syndrome.{{cite journal | vauthors = Papapetropoulos S, Tuchman A, Laufer D, Papatsoris AG, Papapetropoulos N, Mash DC | title = Causes of death in multiple system atrophy | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 78 | issue = 3 | pages = 327–329 | date = March 2007 | pmid = 17308296 | pmc = 2117630 | doi = 10.1136/jnnp.2006.103929 }}

Multiple system atrophy is estimated to affect approximately 5 per 100,000 people. At autopsy, many patients diagnosed during life with Parkinson's disease are found actually to have MSA, suggesting that the actual incidence of MSA is higher than that estimate.{{cite journal | vauthors = Fanciulli A, Wenning GK | title = Multiple-system atrophy | journal = The New England Journal of Medicine | volume = 372 | issue = 3 | pages = 249–263 | date = January 2015 | pmid = 25587949 | doi = 10.1056/NEJMra1311488 }} While some suggest that MSA affects slightly more men than women (1.3:1), others suggest that the two sexes are equally likely to be affected. The condition most commonly presents in persons aged 50–60.

Mesenchymal stem cell therapy may delay the progression of neurological deficits in patients with MSA-cerebellar type.{{cite journal | vauthors = Lee PH, Lee JE, Kim HS, Song SK, Lee HS, Nam HS, Cheong JW, Jeong Y, Park HJ, Kim DJ, Nam CM, Lee JD, Kim HO, Sohn YH | display-authors = 6 | title = A randomized trial of mesenchymal stem cells in multiple system atrophy | journal = Annals of Neurology | volume = 72 | issue = 1 | pages = 32–40 | date = July 2012 | pmid = 22829267 | doi = 10.1002/ana.23612 | s2cid = 5201446 }}

• Nikolai Andrianov was a Soviet/Russian gymnast who held the record for men for the most Olympic medals at 15 (7 gold medals, 5 silver medals, 3 bronze medals) until Michael Phelps surpassed him at the 2008 Beijing Summer Olympics.{{cite news | vauthors = Turner A |title=Olympic Legend Andrianov Dies at 58 |url= http://www.intlgymnast.com/index.php?option=com_content&view=article&id=2414:olympic-legend-andrianov-dies-at-58-&catid=2:news&Itemid=53 |access-date=10 December 2018 |work=International Gymnast Magazine Online |language=en-gb}}
• Todd J. Campbell (1956–2021), United States district judge and counsel to former Vice President Al Gore.{{Cite web|url=https://www.tennessean.com/story/news/2021/04/11/former-us-district-judge-todd-campbell-dies/7150314002/|title=Former U.S. District Judge Todd Campbell, longtime Nashville legal mind and adviser to a vice president, dead at 64| vauthors = Hubbard A, Timms M |website=The Tennessean}}
• Singer and songwriter Johnny Cash wrote in his autobiography that he was diagnosed with Shy–Drager in 1997.{{cite book |title=Cash: The Autobiography |url=https://archive.org/details/cashautobiograph00cash |url-access=registration | vauthors = Cash J, Carr P |date=1998 |orig-year=1997 |isbn=978-0061013577 |location=New York, NY, USA |publisher=HarperCollins Publishers |pages=[https://archive.org/details/cashautobiograph00cash/page/400 400–403] |author-link=Johnny Cash}}
• Ronald Green (1944–2012), American-Israeli basketball player{{Cite web|url=https://www.legacy.com/amp/obituaries/herald/158753446|title=Ronald Green Obituary |date=July 26, 2012 |website=The Miami Herald}}
• Joseph C. Howard Sr. (1922-2000) was the first African American to serve as a United States district judge of the United States District Court for the District of Maryland.{{cite web |url= http://www.house.gov/cummings/articles/art00_37.htm |title=Standing up for justice | vauthors = Cummings E |date=2000-09-30 |publisher=Baltimore AFRO-American |access-date=2018-12-10 |archive-url=https://web.archive.org/web/20080504074002/http://www.house.gov/cummings/articles/art00_37.htm |archive-date=2008-05-04 |url-status=dead }}
• Kenneth More British actor, originally diagnosed with Parkinson's disease.
• Chef Kerry Simon died from complications of MSA.{{Cite news|url=https://www.businessinsider.com/ap-kerry-simon-las-vegas-iron-chef-winner-dies-at-60-2015-9?IR=T|title=Kerry Simon, Las Vegas 'Iron Chef' winner, dies at 60|work=Business Insider|access-date=2018-11-14|archive-date=2018-11-14|archive-url=https://web.archive.org/web/20181114224142/https://www.businessinsider.com/ap-kerry-simon-las-vegas-iron-chef-winner-dies-at-60-2015-9?IR=T|url-status=dead}}
• David Colin Sherrington FRS (1945–2014), noted polymer chemist, who was diagnosed in 2012 and died from pneumonia two years later.
• Karsten Heuer (1968-2024) Canadian Biologist, Conservationist, Filmmaker and Author.

• Olivopontocerebellar atrophy-deafness syndrome

{{Reflist}}

• Medical Textbook: [https://www.springer.com/medicine/neurology/book/978-3-7091-0686-0 "Multiple System Atrophy"] edited by Gregor Wenning and Alessandra Fanciulli

{{Medical resources

| DiseasesDB = 8441

| ICD10 = {{ICD10|G|23|8|g|23}}

| ICD9 = {{ICD9|333.0}}

| ICDO =

| OMIM = 146500

| MedlinePlus = 000757

| eMedicineSubj = neuro

| eMedicineTopic = 671

| MeshID = D019578

}}

{{Medical resources

| ICD10 = {{ICD10|G|23|8|g|20}}

| ICD9 = {{ICD9|333.0}}

| ICDO =

| OMIM =

| MedlinePlus = 000758

| eMedicineSubj = neuro

| eMedicineTopic = 282

| DiseasesDB = 2012

| diseasesDB_mult = {{DiseasesDB2|9208}}

| MeshID = D009849

}}

• {{NINDS|Olivopontocerebellar-Atrophy|Olivopontocerebellar atrophy}}

{{Autonomic diseases}}

{{CNS diseases of the nervous system}}

{{DEFAULTSORT:Multiple System Atrophy}}

Category:Extrapyramidal and movement disorders

Category:Rare diseases

Category:Neurodegenerative disorders

Category:Peripheral nervous system disorders

ca:Síndrome de Shy-Drager

es:Síndrome de Shy-Drager

pt:Síndrome de Shy-Drager

ro:Sindromul Shy-Drager

sl:Shy-Dragerjev sindrom