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Multiple system atrophy: Clinical features and diagnosis

Multiple system atrophy: Clinical features and diagnosis
Authors:
Stewart A Factor, DO
Christine Doss Esper, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Jan 05, 2022.

INTRODUCTION — Multiple system atrophy (MSA) is a unifying term that brings together a group of rare, fatal neurodegenerative syndromes that used to be referred to as olivopontocerebellar atrophy (OPCA), striatonigral degeneration, and Shy-Drager syndrome. These have similar brain pathologies that are characterized by various degrees of autonomic dysfunction, cerebellar abnormalities, parkinsonism, and corticospinal degeneration.

This topic will review the epidemiology, clinical features, and diagnosis of MSA. The prognosis and treatment of MSA are reviewed separately. (See "Multiple system atrophy: Prognosis and treatment".)

Other forms of parkinsonism are discussed elsewhere. (See "Clinical manifestations of Parkinson disease" and "Diagnosis and differential diagnosis of Parkinson disease" and "Corticobasal degeneration" and "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)

HISTORICAL BACKGROUND — In 1900, Dejerine and Thomas provided the first report of sporadic olivopontocerebellar atrophy (OPCA), a disease that later would become a part of the spectrum of MSA [1]. Orthostatic hypotension as a manifestation of autonomic failure was described in 1925 [2]. In 1960, Shy and Drager reported patients with autonomic features of orthostatic syncope, impotence, and bladder dysfunction who went on to develop gait abnormalities, tremor, and fasciculations among other symptoms and signs [3]. This disorder became known as the Shy-Drager syndrome.

Also in 1960, the first cases were reported of a predominantly asymmetric parkinsonian syndrome manifested primarily by akinesia and rigidity [4]. The authors suggested that striatonigral degeneration was the pathologic correlate for these cases.

In 1969, the term "multiple system atrophy" was introduced to encompass all three clinical syndromes: OPCA, Shy-Drager syndrome, and striatonigral degeneration [5]. Striatonigral degeneration was later redefined as MSA with predominant parkinsonism (MSA-P), while OPCA was redefined as MSA with predominant cerebellar ataxia (MSA-C) [6]. When autonomic failure predominates, the term "Shy-Drager syndrome" may be used.

The discovery that glial cytoplasmic inclusions with alpha-synuclein as a major component are the pathologic hallmark of the three clinical syndromes in 1989 confirmed the suspicion that they were actually different manifestations of the same disease [7,8]. Beginning in 1999, consensus groups developed guidelines to define MSA, which were modified in 2008 [6,9-11].

EPIDEMIOLOGY — The estimated annual incidence of MSA in the population >50 years old is approximately 3 per 100,000 [12]. The estimated prevalence of MSA is between 2 to 5 cases per 100,000 population [13,14].

In a meta-analysis of 433 pathologically proven cases of MSA, the mean age of onset was 54 years (range 31 to 78; younger than Parkinson disease) [15]. Similarly, European registry studies have reported onset at a mean age of 56 to 60 years [16-19]. In these registries, MSA affects men and women approximately equally. However, other studies have reported that men are affected two to nine times more often than women [20,21]. This finding may be secondary to earlier recognition of impotence as a major diagnostic feature in men.

Although MSA is considered a sporadic disease, there are several reports of rare patients with probable or possible familial MSA [22-24]. There are no specific racial/ethnic predilections, and the disease has been reported worldwide in American, European, African, and Asian populations.

There are no established environmental risk factors for MSA, but data are limited [8]. As examples, one small case-control study found that patients with MSA had significantly more potential exposures to metals, plastics, organic solvents, and pesticides than controls [25], while another case-control study found that MSA was not associated with exposure to pesticides, organic solvents, or other toxins [26].

PATHOLOGY AND PATHOGENESIS — The cause of MSA is unknown [27]. One postulated mechanism involves prion-like spreading of aberrant alpha-synuclein from neurons to glia through functionally connected networks, thereby leading to glial and myelin dysfunction and an inflammatory cascade that promotes secondary neurodegeneration [28]. There have been a number of experimental studies demonstrating that abnormal alpha-synuclein aggregates might be responsible for the progression of MSA [29,30]. However, this remains controversial and is still an area of investigation [31,32].

The presence of alpha-synuclein messenger RNA (mRNA) in oligodendrocytes as well as glial inclusions and myelin disruption in the central nervous system suggests that MSA is a primary disorder of the glia [27,32,33]. The glial (oligodendroglial) cytoplasmic inclusions that are characteristic of MSA contain hyperphosphorylated alpha-synuclein, tau, ubiquitin, leucine-rich repeat serine/threonine-protein kinase 2, and many other proteins [34-38]. Relocation of tubulin polymerization-promoting phosphoprotein-25-alpha (p25α) from the myelin sheath to the cytoplasm in oligodendrocytes may precede the aggregation of alpha-synuclein [32].

Alpha-synuclein immunostaining is a sensitive marker of inclusion pathology in MSA [8,39]. Neuronal inclusions of various types, including Lewy body-like inclusions, also are present in the majority of patients with MSA [40,41]. In addition, the density of microglia expressing nucleotide-binding domain, leucine-rich repeats-containing family, pyrin domain-containing-3 (NLRP3) inflammasome-related proteins is increased in the putamina of MSA patients [42].

Myelin degeneration is characteristic of MSA. A small case-control study found a significantly greater degree of white matter hyperintensities on magnetic resonance imaging (MRI) scans from patients with MSA compared with scans from patients with Parkinson disease and healthy controls [43]. This finding could be related to the dysfunction and loss of myelin or to cerebral hypoperfusion from orthostatic blood pressure fluctuations in MSA.

The pathologic distribution of glial cytoplasmic inclusions, along with the degree of neuronal loss within specific regions of the neuraxis, primarily determines the clinical presentation of MSA. In addition, neuronal cell loss appears to be significantly correlated with the pathologic burden of glial cytoplasmic inclusions and disease duration [44]. Typical sites of pathologic involvement include the putamen, caudate nucleus, substantia nigra, locus ceruleus, pontine nuclei, inferior olivary nucleus, Purkinje cell layer of the cerebellum, and intermediolateral cell columns [45].

Autonomic dysfunction is secondary to loss of cells in the intermediolateral cell columns [46,47] and loss of catecholaminergic neurons of the C1 area of the ventrolateral medulla (VLM) [48]. This is manifested by severe variability in blood pressure and heart rate, orthostatic hypotension, syncope, and postprandial hypotension. Arginine-vasopressin release from magnocellular hypothalamic neurons is impaired; this may be mediated by loss of A1 neurons in the caudal VLM.

In idiopathic Parkinson disease, positron emission tomography (PET) imaging studies have indicated that dysautonomia is caused by peripheral nervous system dysfunction, particularly myocardial sympathetic denervation [49]. By contrast, the peripheral autonomic system appears to be spared in MSA [50]. Some persistence of autonomic tone may be responsible for the frequently observed supine hypertension in MSA.

Bladder abnormalities in MSA include urinary incontinence and retention. Mechanisms leading to these include detrusor hyperreflexia from loss of inhibitory input to the pontine micturition center, loss of corticotropin-releasing factor neurons in the pontine micturition area [48], and bladder atonia primarily from severe damage to Onuf's nucleus in the sacral spinal cord. Damage to Onuf's nucleus is also the most likely cause of erectile dysfunction in men. Bowel dysmotility is frequently seen in patients with MSA [51], as is thermoregulatory dysfunction [8]. (See 'Dysautonomia' below.)

Motor abnormalities seen in MSA with predominant parkinsonism (MSA-P) are due primarily to neuronal loss and gliosis in the substantia nigra, putamen, caudate, and globus pallidus [4]. One of the features that distinguishes MSA and other atypical parkinsonian syndromes (ie, Parkinson-plus syndromes) from idiopathic Parkinson disease is the lack of dramatic and sustained response to levodopa. The extent of putaminal involvement may determine the poor response to levodopa [44]. (See 'Levodopa responsiveness' below.)

In contrast to MSA-P, the cerebellar ataxia and pyramidal signs that characterize the MSA with predominant cerebellar ataxia (MSA-C) subtype are secondary to degeneration of the cerebellar Purkinje cells, middle cerebellar peduncles, inferior olivary nuclei, basis pontis, and pontine nuclei. However, a majority of patients with MSA-P probably have subclinical loss of nigral neurons based upon findings from 123I-FP-CIT single-photon emission computed tomography (SPECT) imaging [52].

Loss of cholinergic mesopontine neurons, combined with loss of locus ceruleus neurons and preservation of rostral raphe neurons, may contribute to rapid eye movement (REM) sleep abnormalities often seen in MSA [48]. Respiratory abnormalities may reflect loss of cholinergic neurons in the arcuate nucleus of the ventral medulla [48]. Respiratory stridor, abnormal nocturnal ventilation, and pseudobulbar features are possibly secondary to brainstem pathology, and may involve the nucleus ambiguus [8].

Genetics — The role of genetics in the pathogenesis of MSA is undefined. One report found that mutations in the COQ2 gene were associated with familial MSA in two Japanese families [53]. In other studies, MSA was associated with copy number loss of the SHC2 gene [54] and with genetic variants of the synuclein alpha (SNCA) gene [55,56]. A subsequent genome-wide association study from Europe and North America that compared 918 patients with MSA and 3864 controls found no significant loci, and in particular did not find an association of MSA with genetic variation in COQ2 or SNCA [57]. Rather, the microtubule-associated protein tau (MAPT) was the only gene that appeared to be associated with MSA, and two other studies suggest that MAPT haplotypes H1x and H1 may be associated with an increased risk of MSA [58,59]. The role of tau isoforms in MSA is currently unknown.

Genetic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and the glucocerebrosidase (GBA) gene, both common genetic causes of Parkinson disease, can present as MSA clinically as well as neuropathologically [60-62]. Another study identified a new coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) mutation in a patient with MSA [63].

CLINICAL CHARACTERISTICS — The main clinical features of MSA are akinetic-rigid parkinsonism, autonomic failure including urogenital dysfunction, cerebellar ataxia, and pyramidal signs in varying combinations. The onset of disease is marked by the initial clinical manifestation of any of its characteristic motor or autonomic features [64]. However, the neuropathologic changes probably begin several years before the disease becomes symptomatic. (See 'Pathology and pathogenesis' above.)

Motor involvement — The motor presentations of MSA are classified into two separate but overlapping clinical subtypes [6,8,20]:

MSA with predominant parkinsonism (MSA-P) subtype

MSA with predominant cerebellar ataxia (MSA-C) subtype

In most studies from Europe and North America, cases of MSA-P outnumber MSA-C by between two and four to one [18,65]. This contrasts with studies from Japan, which report MSA-C as more common than MSA-P [66].

The predominant motor feature can change over time with disease progression [11]. Thus, the designation of MSA-P or MSA-C refers to the predominant motor problem at the time the patient is evaluated. As an example, in a European study of 437 patients from 19 centers, the proportion of patients classified as MSA-P and MSA-C was 68 and 32 percent, respectively [18]. However, among the entire cohort, parkinsonism and cerebellar ataxia were present in 87 and 64 percent, respectively.

Parkinsonism in MSA-P is characterized by akinesia/bradykinesia, rigidity, postural instability, and/or an irregular jerky postural and action tremor. Up to two-thirds of patients with MSA have this tremor involving the arms. Although much less common than in idiopathic Parkinson disease, rest tremor occurs in as many as one-third of patients with MSA-P [16]. Other warning signs that herald parkinsonism in MSA include postural instability and falls (usually within three years of motor onset), pyramidal signs including extensor plantar responses, and rapid progression regardless of dopaminergic treatment [8,66].

Additional movement disorders associated with MSA-P may include stimulus-sensitive cortical myoclonus, hemiballism and chorea, and dystonia unrelated to dopaminergic therapy [67-69]. Specific types of dystonia include orofacial dystonia or dyskinesia, occasionally resembling "risus sardonicus" (spasm of the facial muscles producing a distorted grinning expression), and Pisa syndrome (subacute axial dystonia with severe lateral flexion of the trunk, head, and neck).

Camptocormia (severe anterior flexion of the spine) (figure 1) and disproportionate antecollis (figure 2) are common abnormalities of posture in MSA [8,70]. The anterocollis, in particular, is characteristic of MSA, although it can occur in other forms of degenerative parkinsonism [71-73].

The cause of camptocormia and anterocollis in MSA is heterogeneous. While some authors believe that they represent forms of axial dystonia [74], there are other data to suggest that myopathy is the cause, at least in certain cases [75,76]. Electromyography usually clarifies the picture, although biopsy may be necessary when the diagnosis is uncertain. However, it is not entirely clear what a biopsy of normal neck muscle should look like in patients with parkinsonism.

In contrast to MSA-P, the motor features of MSA-C involve predominant cerebellar dysfunction that manifests as gait ataxia, limb ataxia, ataxic dysarthria, and cerebellar disturbances of eye movements [8]. Ocular abnormalities may include gaze-evoked nystagmus, impaired smooth pursuits with saccadic intrusion, and/or ocular dysmetria.

Dysphagia is a prominent symptom of both types of MSA [77].

The speech pattern of patients with MSA is also characteristic. In addition to the hypophonic monotony often seen in idiopathic Parkinson disease, patients with MSA-P also have an increase in pitch and a quivering, strained element to their speech [8]. By contrast, patients with MSA-C have a more typical cerebellar scanning dysarthria.

Dysautonomia — Dysautonomia is a feature of both parkinsonian and cerebellar MSA presentations [8]. Among patients in a large European MSA registry, symptomatic dysautonomia was present in almost all, with high rates of urinary dysfunction (83 percent) and symptomatic orthostatic hypotension (75 percent) [18]. Up to 80 percent of patients have decreased sweating, including nearly half with anhidrosis [78].

Nearly all men with MSA develop early erectile dysfunction [8]. The most frequently reported urinary symptoms are voiding difficulty (80 percent), nocturia (74 percent), urgency (63 percent), incontinence (63 percent), diurnal frequency (45 percent), nocturnal enuresis (19 percent), and urinary retention (8 percent) [79]. Although these features are also seen in idiopathic Parkinson disease, they generally begin earlier and are more profound in MSA. As an example, a study comparing 52 patients with MSA and matched patients with Parkinson disease noted that urinary dysfunction appeared in less than two years with MSA but after five years with Parkinson disease [80]. Detrusor underactivity with dysuria was observed within four years in 58 percent of patients with MSA and thereafter in 76 percent. By contrast, the frequency of constipation in MSA is similar to that seen in idiopathic Parkinson disease [8].

In the natural history of MSA, orthostatic hypotension usually emerges after urogenital symptoms appear. In a series of 100 patients with MSA, symptomatic orthostatic hypotension was present in 68 percent and was severe in 15 percent [20]. The clinical diagnosis of probable MSA requires the presence of an orthostatic decrease of blood pressure. (See 'Diagnostic criteria' below.)

Sleep and breathing disorders — Sleep and breathing abnormalities are common in MSA. A retrospective study of 45 patients with MSA who underwent video polysomnography revealed sleep-related breathing disorders in 62 percent, including stridor (38 percent), obstructive sleep apnea (31 percent), central sleep apnea (9 percent), and ataxic breathing (n = 1) [81].

At least two-thirds of patients have rapid eye movement (REM) sleep behavior disorder (RBD) [82,83]. RBD is characterized by loss of the usual muscle atony during REM sleep, leading patients to act out their dreams. The content of the dreams is often vivid, violent, or frightening. Patients may talk or shout during sleep and may strike out at their bed partner. The emergence of RBD may precede the motor manifestations of MSA by several years or even decades, in some cases [84,85]. Patients with early RBD may be more likely to have an autonomic onset of MSA and less likely to manifest parkinsonism [83]. RBD tends to decrease in severity as the disease progresses [65]. (See "Rapid eye movement sleep behavior disorder".)

Nocturnal or diurnal laryngeal stridor occurs in approximately 15 to 40 percent of patients with MSA [86]. It is a fairly specific feature of MSA, which is uncommon in idiopathic Parkinson disease and other neurodegenerative syndromes [65]. Stridor is caused by laryngospasm with impaired or paradoxical vocal cord abduction. The sound is high-pitched and occurs with inspiration as air vibrates the narrowed vocal folds. Families may mistake it for loud snoring. Stridor usually begins during sleep but can be present during the daytime in advanced cases. Early emergence of stridor has been associated with shorter survival in patients with MSA [87], and it may be a risk factor for sudden death in sleep. Patients with stridor should be referred to otolaryngology and for evaluation. (See "Multiple system atrophy: Prognosis and treatment", section on 'Stridor'.)

Both excessive daytime sleepiness and restless legs syndrome are present in nearly 30 percent of patients with MSA, rates that are similar to or greater than those seen in Parkinson disease [88].

Cognitive function — Cognitive function in MSA tends to be relatively well preserved compared with idiopathic Parkinson disease and other atypical parkinsonian syndromes, possibly reflecting a lesser degree of cortical involvement in MSA [89] and the younger age of onset. Nevertheless, although cognitive impairment in MSA is uncommon, it does occur and its presence does not exclude MSA as a clinical diagnosis in patients who have classic symptoms and signs of the disorder.

A multicenter European study evaluated a prospective cohort of 372 patients with a clinical diagnosis of MSA and found cognitive impairment in approximately 20 percent, predominantly involving diminished verbal fluency, perseveration, and executive dysfunction, as seen in Parkinson disease and progressive supranuclear palsy [90]. One limitation of this report is that few patients had pathologic confirmation of the clinical diagnosis, and among those who did, the clinical diagnosis of MSA was proved wrong in 35 percent of those with cognitive impairment compared with 5 percent of those without cognitive impairment. Thus, this study probably overestimated the rate of cognitive impairment in MSA.

A small case-control study found that patients with MSA-P had cognitive impairments involving visuospatial and constructional function, verbal fluency, and executive function, while those with MSA-C had impairments only in visuospatial and constructional function [91].

Patients with MSA can develop emotional incontinence (also called pseudobulbar affect), characterized by crying inappropriately without sadness or laughing inappropriately without mirth. This manifestation is also seen, perhaps more commonly, in progressive supranuclear palsy.

Other features — Patients with MSA may have an associated Raynaud phenomenon (an exaggerated vascular response to cold temperature or emotional stress) and/or cold, dusky extremities that blanch on pressure with poor circulatory return. These symptoms may be provoked by ergot drugs. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

MSA is associated with high rates of anxiety, depression, and fatigue [92,93]. In one study of 286 patients with MSA, probable depression and probable anxiety were present in 43 and 37 percent, respectively [92].

Olfactory dysfunction is generally mild in MSA [94]; a small case-control study found that olfactory dysfunction in MSA is less severe than that seen in Parkinson disease [95].

Neuroimaging — Brain magnetic resonance imaging (MRI) in patients with MSA-P and MSA-C may reveal atrophy of the putamen, pons, and middle cerebellar peduncles [11,96,97]. On T2 MRI sequences, signal changes include hypointensity of the posterior putamen (also described as a slit-like void), a hyperintense lateral putaminal rim, and hyperintensities of the middle cerebellar peduncles. These changes are supportive of the diagnosis of MSA rather than idiopathic Parkinson disease. However, they are not present in all patients with MSA. Furthermore, they are not specific for differentiating MSA from other atypical parkinsonian syndromes. However, machine-learning techniques examining volumes of the cerebellum, brainstem, and putamen from T1-weighted images may become a useful strategy in improving diagnosis [98].

The "hot cross bun sign" refers to hyperintense T2 signal in the shape of a cross within the pons that arises from degeneration of transverse pontocerebellar fibers [11,96,99]. However, this is a nonspecific finding that has also been described in patients with other causes of parkinsonism [99-101].

Diffusion-weighted imaging (DWI) MRI in patients with MSA shows increased diffusivity (high apparent diffusion coefficient [ADC] values) in the putamen, a finding that is sometimes observed in progressive supranuclear palsy [96]. In one systematic review, putaminal diffusivity had high sensitivity and specificity (90 and 93 percent) for distinguishing between patients with MSA-P and idiopathic Parkinson disease [102]. Preliminary data suggest that this technique can also be used to monitor disease progression in MSA [103].

Positron emission tomography using 18-F fluorodeoxyglucose (FDG-PET) in patients with MSA may reveal regional glucose hypometabolism in the striatum, brainstem, and cerebellum and a specific MSA-related metabolic pattern, but the true sensitivity and specificity of these findings for differentiating MSA from Parkinson disease remains uncertain [96].

Striatal dopamine transporter imaging using single-photon emission computed tomography (SPECT; eg, 123I-FP-CIT SPECT scan or DaTscan) can reliably distinguish patients with Parkinson disease and other parkinsonian syndromes from controls or patients with essential tremor, but it cannot differentiate Parkinson disease and the parkinsonian syndromes from one another. However, it may be helpful in diagnosing patients with pure ataxia, autonomic symptoms, or RBD. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan'.)

123I-metaiodobenzylguanidine (MIBG, iobenguane) imaging of the heart demonstrates postganglionic abnormalities in patients with Parkinson disease but not those with MSA [104,105]. This cardiac imaging technique shows promise for differentiating the two diseases, but its clinical utility has yet to be established.

DIAGNOSIS — The diagnosis of MSA is based upon the clinical features. No laboratory or imaging studies are diagnostic, particularly since findings are often normal or equivocal in early disease.

Levodopa responsiveness should be tested to help distinguish MSA from idiopathic Parkinson disease, although making a distinction can be complicated. For a diagnostic trial of levodopa to be valid in this setting, it is essential that the daily dose be high enough (900 to 1000 mg) in order to avoid a false-negative result. Furthermore, some patients who later in the clinical course of progressive parkinsonism meet diagnostic criteria for MSA will show an early positive response to levodopa, thereby producing a falsely positive diagnosis of Parkinson disease, as discussed below. (See 'Levodopa responsiveness' below.)

Neuroimaging can be helpful in excluding other conditions and may show signs such as putaminal atrophy, slit-like signal change at the posterolateral putaminal margin, and hypointensity of the putamen relative to the globus pallidus. (See 'Neuroimaging' above.)

Urethral or anal sphincter electromyography can support the diagnosis of MSA if the results show chronic reinnervation with markedly prolonged motor units [51,106,107]. However, this is a painful procedure, and some studies suggest these findings are not specific for MSA [108].

Levodopa responsiveness — In the early stages, MSA with predominant parkinsonism (MSA-P) may be difficult to distinguish from idiopathic Parkinson disease [8].

An excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis of idiopathic Parkinson disease. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Response to dopaminergic therapy'.)

By contrast, a poor or unsustained response to levodopa therapy is generally observed in patients with MSA [44,109,110]. While open-label and retrospective studies suggest transient benefit from levodopa in 30 to 50 percent of patients with MSA [16,20,44,109-114], levodopa does not provide long-term benefit in MSA, and the loss of responsiveness can occur abruptly. However, treatment must be individualized since some patients will function better on levodopa than without it.

Patients with young-onset disease (before age 40 years) may be more likely to show levodopa responsiveness than patients with later-onset MSA [115].

Levodopa responsiveness is tested by administering levodopa combined with a peripheral decarboxylase inhibitor (eg, levodopa-carbidopa) in escalating doses up to 1000 mg of levodopa daily as necessary and tolerated over a three-month period [8]. A positive response requires a clinically significant improvement in motor symptoms, defined objectively as a 30 percent or more improvement in the motor component of the Unified Parkinson Disease Rating Scale (UPDRS) [6].

As in idiopathic Parkinson disease, levodopa treatment may trigger or exacerbate orthostatic hypotension in patients with MSA [8]. Levodopa use also can result in motor fluctuations and dyskinesia. As an example, a case series that included 18 patients with MSA-P reported that levodopa-induced dyskinesia developed in 12 (67 percent) [116]. Levodopa-induced dyskinesia in patients with MSA is not uncommonly restricted to the neck or face, and often consists of sustained dystonic spasms. Levodopa-induced unilateral facial dystonic spasms are particularly suggestive of MSA [117]. Some patients with MSA may develop generalized dyskinesia as seen in idiopathic Parkinson disease.

Diagnostic criteria — Revised diagnostic criteria set forth in the 2008 MSA consensus statement are shown in the tables (table 1 and table 2 and table 3 and table 4) [11].

A diagnosis of definite MSA is based upon postmortem pathology showing alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures [11].

The clinical diagnosis of probable MSA during life requires the following features (table 1) [11]:

A sporadic, progressive, adult-onset (>30 years old) disease

Autonomic failure involving either urinary incontinence (inability to control the release of urine from the bladder, with erectile dysfunction in males) or an orthostatic blood pressure decrease within three minutes of standing by ≥30 mmHg systolic or ≥15 mmHg diastolic

Either poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or a cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction)

The clinical diagnosis of possible MSA requires a sporadic, progressive, adult-onset disease with either parkinsonism or cerebellar ataxia and at least one feature suggesting dysautonomia plus one additional supporting feature (table 2 and table 3) [11].

Neuroimaging criteria — Neuroimaging correlates of MSA lack sufficient sensitivity and specificity to be used as reliable markers of probable MSA. (See 'Neuroimaging' above.)

Nevertheless, current diagnostic criteria regard atrophy of putamen, middle cerebellar peduncle, or pons on magnetic resonance imaging (MRI) as supportive features for possible MSA-P or MSA with predominant cerebellar ataxia (MSA-C) [11,96]. Additional supportive features for MSA subtypes are as follows:

In a patient with parkinsonian features but no cerebellar ataxia, hypometabolism of putamen, brainstem, or cerebellum on 18-F fluorodeoxyglucose-positron emission tomography (FDG-PET) is considered to be a supportive feature for possible MSA-P.

In a patient with cerebellar ataxia lacking parkinsonian features, two additional imaging features are considered to be supportive for possible MSA-C:

Hypometabolism of the putamen on FDG-PET

Presynaptic dopaminergic denervation in the striatum on functional imaging with single-photon emission computed tomography (SPECT) or PET

Genetic testing — The utility of genetic testing in MSA is uncertain. However, limited data suggest that genetic testing can uncover cases of spinocerebellar ataxia (SCA) that mimic MSA. In a retrospective report from Korea, 302 patients with a clinical diagnosis of probable or possible MSA had genetic testing for some of the more common types of SCA [118]. Those with MSA-C were more likely to be tested. Most patients, irrespective of clinical phenotype, had cerebellar atrophy on MRI. Mutations in SCA genes (table 5) were found in 22 patients (7 percent) with trinucleotide expansion repeats in genes responsible for SCA17 (n = 13), SCA2 (n = 3), SCA6 (n = 3), SCA1 (n = 1), SCA3 (n = 1), and dentatorubral pallidoluysian atrophy (n = 1). Seventeen of the 22 patients had cerebellar findings on neurologic examination (ie, suggesting MSA-C or mixed subtype), whereas only five were diagnosed clinically with MSA-P. Among the 22 SCA cases, the mean age at onset was 59 years, similar to the patients without SCA mutations, and only three patients had a family history of cerebellar ataxia. (See "The spinocerebellar ataxias".)

DIFFERENTIAL DIAGNOSIS — It is important to distinguish MSA from idiopathic Parkinson disease and from other atypical parkinsonian syndromes, mainly progressive supranuclear palsy and corticobasal degeneration. In clinicopathologic studies, the accuracy of a clinical diagnosis of MSA ranges from 60 to 80 percent when compared with autopsy findings [119-121]. The distinction between MSA with predominant parkinsonism (MSA-P) and progressive supranuclear palsy can be particularly difficult during life [122]. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

The primary feature that clinically distinguishes MSA-P from idiopathic Parkinson disease in most cases is the lack of a sustained and dramatic reduction in clinical symptoms and signs with levodopa therapy (see 'Levodopa responsiveness' above). Additional clues include the presence of other characteristic features of MSA, such as autonomic failure, the jerky postural tremor, ataxia (in MSA with predominant cerebellar ataxia [MSA-C]), and pyramidal tract signs [115,121].

The presence of vertical eye movement abnormalities and the absence of orthostatic hypotension suggest progressive supranuclear palsy. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)

Apraxia suggests corticobasal degeneration. (See "Corticobasal degeneration".)

However, there is overlap among these conditions. MSA may sometimes present with the phenotype of progressive supranuclear palsy, including vertical eye movement abnormalities [121,122]. In addition, patients with a pure akinetic-rigid syndrome may be impossible to diagnose.

Among patients with idiopathic adult-onset cerebellar ataxia, 21 to 33 percent will meet clinical criteria for MSA-C [65,123,124]. Other disorders may present with a combination of cerebellar and parkinsonian features [118,125]:

Various types of spinocerebellar ataxia (SCA), including SCA2, SCA3, SCA6, and SCA17 (see "The spinocerebellar ataxias")

Late-onset Friedreich ataxia (see "Friedreich ataxia")

The fragile X tremor/ataxia syndrome (see "The spinocerebellar ataxias", section on 'Fragile X-associated tremor/ataxia syndrome')

These disorders may be misdiagnosed as MSA-C or vice-versa [123].

Pure autonomic failure should be considered if autonomic symptoms are the predominant feature of the disorder and motor involvement is limited or absent. Pure autonomic failure is associated with slower functional deterioration and a better prognosis than MSA [126].

Mitochondrial disorders also affect multiple systems, but often include other neurologic features such as myopathy, optic neuropathy or retinopathy, and deafness. Systemic features of mitochondrial disorders may include cardiomyopathy and diabetes. (See "Mitochondrial myopathies: Clinical features and diagnosis".)

SUMMARY AND RECOMMENDATIONS

Multiple system atrophy (MSA) encompasses three clinical syndromes: MSA with predominant cerebellar ataxia (MSA-C; previously known as olivopontocerebellar atrophy [OPCA]), MSA with predominant parkinsonism (MSA-P; previously known as striatonigral degeneration), and Shy-Drager syndrome. (See 'Historical background' above.)

The estimated annual incidence of MSA in the population >50 years old is approximately 3 per 100,000. The mean age of onset ranges from 54 to 60 years. There appears to be no racial or gender predilection. (See 'Epidemiology' above.)

The cause of MSA is unknown, though one postulated mechanism involves prion-like spreading of aberrant alpha-synuclein through functionally connected networks. Glial cytoplasmic inclusions are the pathologic hallmark of MSA and contain alpha-synuclein, tau, and ubiquitin. Typical sites of pathologic involvement include the putamen, caudate nucleus, substantia nigra, locus ceruleus, pontine nuclei, inferior olivary nucleus, Purkinje cell layer of the cerebellum, and intermediolateral cell columns. (See 'Pathology and pathogenesis' above.)

The main clinical features of MSA are akinetic-rigid parkinsonism, autonomic failure, urogenital dysfunction, cerebellar ataxia, and pyramidal signs in varying combinations. (See 'Clinical characteristics' above.)

The motor features of MSA-P are characterized by akinesia/bradykinesia, rigidity, postural instability, and/or an irregular jerky postural and action tremor. The motor features of MSA-C involve predominant cerebellar dysfunction that manifests as gait ataxia, limb ataxia, ataxic dysarthria, and cerebellar disturbances of eye movements. (See 'Motor involvement' above.)

Dysautonomia is a feature of both MSA-P and MSA-C. Nearly all men with MSA develop early erectile dysfunction. Other common early MSA symptoms include increased urinary frequency, urgency, incontinence, or incomplete bladder emptying. Orthostatic hypotension usually emerges after urogenital symptoms appear. (See 'Dysautonomia' above.)

The diagnosis of MSA is based upon the clinical features. No laboratory or imaging studies are diagnostic. Lack of sustained response to levodopa can help to distinguish MSA from idiopathic Parkinson disease, but transient benefit from levodopa is observed in 30 to 50 percent of patients with MSA. (See 'Diagnosis' above.)

It is important to distinguish MSA from idiopathic Parkinson disease and other atypical parkinsonian syndromes (progressive supranuclear palsy and corticobasal degeneration). (See 'Differential diagnosis' above.)

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Topic 4890 Version 25.0

References

1 : L'atrophie olivo-ponto-cérébelleuse

2 : Postural hypotension: a report of three cases

3 : A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study.

4 : Striopallidal-nigral degeneration. An hitherto undescribed lesion in paralysis agitans

5 : Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.

6 : Consensus statement on the diagnosis of multiple system atrophy.

7 : Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome).

8 : Multiple system atrophy.

9 : Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology.

10 : Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology.

11 : Second consensus statement on the diagnosis of multiple system atrophy.

12 : Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990.

13 : Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study.

14 : Prevalence of multiple system atrophy.

15 : Survival of patients with pathologically proven multiple system atrophy: a meta-analysis.

16 : The European Multiple System Atrophy-Study Group (EMSA-SG).

17 : Features of probable multiple system atrophy patients identified among 4770 patients with parkinsonism enrolled in the multicentre registry of the German Competence Network on Parkinson's disease.

18 : Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry.

19 : The natural history of multiple system atrophy: a prospective European cohort study.

20 : Clinical features and natural history of multiple system atrophy. An analysis of 100 cases.

21 : Epidemiological evidence on multiple system atrophy.

22 : Multiplex families with multiple system atrophy.

23 : Definite multiple system atrophy in a German family.

24 : Probable hereditary multiple system atrophy-autonomic (MSA-A) in a family in the United States.

25 : Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation.

26 : Risk factors of multiple system atrophy: a case-control study in French patients.

27 : Multiple system atrophy: a primary oligodendrogliopathy.

28 : Neuropathology of multiple system atrophy: new thoughts about pathogenesis.

29 : Evidence forα-synuclein prions causing multiple system atrophy in humans with parkinsonism.

30 : MSA prions exhibit remarkable stability and resistance to inactivation.

31 : Is Multiple System Atrophy a New Prion Disorder?

32 : Multiple System Atrophy: Recent Developments and Future Perspectives.

33 : Myelin degeneration in multiple system atrophy detected by unique antibodies.

34 : Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer's disease.

35 : Widespread alterations of alpha-synuclein in multiple system atrophy.

36 : Increased tau immunoreactivity in oligodendrocytes following human stroke and head injury.

37 : Ubiquitin-positive inclusions in different types of multiple system atrophy: distribution and specificity.

38 : Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update.

39 : [Occurrence of argyrophilic grains in multiple system atrophy: histopathological examination of 26 autopsy cases].

40 : Expanding the spectrum of neuronal pathology in multiple system atrophy.

41 : The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology.

42 : NLRP3 Inflammasome-Related Proteins Are Upregulated in the Putamen of Patients With Multiple System Atrophy.

43 : White matter hyperintensities in patients with multiple system atrophy.

44 : The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations.

45 : The definition of multiple system atrophy: a review of recent developments.

46 : Quantitative study of lateral horn cells in 15 cases of multiple system atrophy.

47 : Lateral horn cells in progressive autonomic failure.

48 : Brainstem in multiple system atrophy: clinicopathological correlations.

49 : Orthostatic hypotension from sympathetic denervation in Parkinson's disease.

50 : The nature of the autonomic dysfunction in multiple system atrophy.

51 : Colonic transit time, sphincter EMG, and rectoanal videomanometry in multiple system atrophy.

52 : Subclinical nigrostriatal dopaminergic denervation in the cerebellar subtype of multiple system atrophy (MSA-C).

53 : Mutations in COQ2 in familial and sporadic multiple-system atrophy.

54 : 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.

55 : SNCA variants are associated with increased risk for multiple system atrophy.

56 : Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

57 : A genome-wide association study in multiple system atrophy.

58 : MAPT haplotype diversity in multiple system atrophy.

59 : MAPT H1 haplotype is a risk factor for essential tremor and multiple system atrophy.

60 : LRRK2 p.Ile1371Val Mutation in a Case with Neuropathologically Confirmed Multi-System Atrophy.

61 : Early-onset pathologically proven multiple system atrophy with LRRK2 G2019S mutation.

62 : Frequency of GBA variants in autopsy-proven multiple system atrophy.

63 : A new CHCHD2 mutation identified in a southern italy patient with multiple system atrophy.

64 : Multiple system atrophy: an update.

65 : How to diagnose multiple system atrophy.

66 : Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

67 : Stimulus-sensitive myoclonus in akinetic-rigid syndromes.

68 : Postural and action myoclonus in patients with parkinsonian type multiple system atrophy.

69 : Hemiballism and chorea in a patient with parkinsonism due to a multisystem degeneration.

70 : Disproportionate antecollis in multiple system atrophy.

71 : Dropped head syndrome in Parkinson's disease.

72 : Myopathy causing camptocormia in idiopathic Parkinson's disease: a multidisciplinary approach.

73 : Camptocormia in idiopathic Parkinson's disease: a focal myopathy of the paravertebral muscles.

74 : Camptocormia, head drop and other bent spine syndromes: heterogeneous etiology and pathogenesis of Parkinsonian deformities.

75 : Parkinsonism and neck extensor myopathy: a new syndrome or coincidental findings?

76 : Focal myopathy as a cause of anterocollis in Parkinsonism.

77 : Olivopontocerebellar atrophy. A review of 117 cases.

78 : Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests.

79 : Prevalence and treatment of LUTS in patients with Parkinson disease or multiple system atrophy.

80 : Urodynamic analysis in multiple system atrophy: characterisation of detrusor-sphincter dyssynergia.

81 : Stridor combined with other sleep breathing disorders in multiple system atrophy: a tailored treatment?

82 : REM sleep behavior disorders in multiple system atrophy.

83 : Progression and prognosis in multiple system atrophy presenting with REM behavior disorder.

84 : REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century.

85 : Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: a multicenter study.

86 : Stridor in multiple system atrophy: Consensus statement on diagnosis, prognosis, and treatment.

87 : Early stridor onset and stridor treatment predict survival in 136 patients with MSA.

88 : Excessive daytime sleepiness in multiple system atrophy (SLEEMSA study).

89 : Subcortical dementia revisited: similarities and differences in cognitive function between progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA).

90 : Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy.

91 : Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P.

92 : A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy.

93 : Fatigue in Patients With Multiple System Atrophy: A Prospective Cohort Study.

94 : Olfaction and Parkinson's syndromes: its role in differential diagnosis.

95 : Differentiating Parkinson's disease from multiple system atrophy by [123I]meta-iodobenzylguanidine myocardial scintigraphy and olfactory test.

96 : Proposed neuroimaging criteria for the diagnosis of multiple system atrophy.

97 : Striatonigral degeneration: iron deposition in putamen correlates with the slit-like void signal of magnetic resonance imaging.

98 : Diagnostic potential of automated subcortical volume segmentation in atypical parkinsonism.

99 : Teaching neuroImage: MRI in multiple system atrophy: "hot cross bun" sign and hyperintense rim bordering the putamina.

100 : "Hot cross bun" sign in a patient with parkinsonism secondary to presumed vasculitis.

101 : Pontine MRI hyperintensities ("the cross sign") are not pathognomonic for multiple system atrophy (MSA).

102 : Diffusion-weighted MRI distinguishes Parkinson disease from the parkinsonian variant of multiple system atrophy: A systematic review and meta-analysis.

103 : Progression of striatal and extrastriatal degeneration in multiple system atrophy: a longitudinal diffusion-weighted MR study.

104 : Whole body and cardiac metaiodobenzylguanidine kinetics in Parkinson disease and multiple system atrophy: implications for the diagnostic role of imaging.

105 : Abnormal cardiac [(123)I]-meta-iodobenzylguanidine uptake in multiple system atrophy.

106 : Value of sphincter electromyography in the diagnosis of multiple system atrophy.

107 : Genitourinary dysfunction in multiple system atrophy: clinical features and treatment in 62 cases.

108 : Quantitative electromyography of the external anal sphincter in Parkinson's disease and multiple system atrophy.

109 : The dopaminergic response in multiple system atrophy.

110 : Response to L-DOPA in multiple system atrophy.

111 : Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria.

112 : Striatonigral degeneration. A clinicopathological study.

113 : Variations in axial, proximal, and distal motor response to L-dopa in multisystem atrophy and Parkinson's disease.

114 : Levodopa efficacy and pathological basis of Parkinson syndrome.

115 : Young-onset multiple system atrophy: Clinical and pathological features.

116 : Dystonia in multiple system atrophy.

117 : Unilateral facial dystonia in multiple system atrophy

118 : Should genetic testing for SCAs be included in the diagnostic workup for MSA?

119 : When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients.

120 : Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study.

121 : Identification of multiple system atrophy mimicking Parkinson's disease or progressive supranuclear palsy.

122 : Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases.

123 : The aetiology of sporadic adult-onset ataxia.

124 : Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy.

125 : "Atypical" atypical parkinsonism: new genetic conditions presenting with features of progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy-a diagnostic guide.

126 : Progression and prognosis in pure autonomic failure (PAF): comparison with multiple system atrophy.