The Cerebellum (2023) 22:825–839

https://doi.org/10.1007/s12311-022-01453-w

ORIGINAL ARTICLE

A Review on the Clinical Diagnosis of Multiple System Atrophy

Iva Stankovic1 · Alessandra Fanciulli2 · Victoria Sidoroff2 · Gregor K. Wenning2

Accepted: 30 July 2022 / Published online: 19 August 2022

© The Author(s) 2022

Abstract
Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative disorder with major diagnostic chal-
lenges. Aiming for a better diagnostic accuracy particularly at early disease stages, novel Movement Disorder Society criteria
for the diagnosis of MSA (MDS MSA criteria) have been recently developed. They introduce a neuropathologically estab-
lished MSA category and three levels of clinical diagnostic certainty including clinically established MSA, clinically probable
MSA, and the research category of possible prodromal MSA. The diagnosis of clinically established and clinically probable
MSA is based on the presence of cardiovascular or urological autonomic failure, parkinsonism (poorly L-Dopa-responsive
for the diagnosis of clinically established MSA), and cerebellar syndrome. These core clinical features need to be associated
with supportive motor and non-motor features (MSA red flags) and absence of any exclusion criteria. Characteristic brain
MRI markers are required for a diagnosis of clinically established MSA. A research category of possible prodromal MSA is
devised to capture patients manifesting with autonomic failure or REM sleep behavior disorder and only mild motor signs
at the earliest disease stage. There is a number of promising laboratory markers for MSA that may help increase the overall
clinical diagnostic accuracy. In this review, we will discuss the core and supportive clinical features for a diagnosis of MSA
in light of the new MDS MSA criteria, which laboratory tools may assist in the clinical diagnosis and which major differential
diagnostic challenges should be borne in mind.

Keywords Multiple system atrophy · Neurogenic orthostatic hypotension · Urogenital failure · Parkinsonism · Cerebellar
ataxia

Introduction
Multiple system atrophy (MSA) is a rare, fatal, rapidly pro-
gressive neurodegenerative disease of adulthood, character-
ized by severe autonomic failure, poorly L-Dopa-responsive
parkinsonism, cerebellar ataxia, and pyramidal signs in any
combination [1]. It is classified as MSA-parkinsonian (MSA-
P), if parkinsonism prevails, and MSA-cerebellar (MSA-C),
if cerebellar features predominate. The MSA-C variant typi-
cally outnumbers the MSA-P one in East Asian natives: large
cohorts of Japanese, Korean, and Chinese reported a MSA-C
phenotype in up to 73% of examined patients [2–6], with
* Alessandra Fanciulli
alessandra.fanciulli@i-med.ac.at
1
Neurology Clinic, University Clinical Center of Serbia,
Faculty of Medicine, University of Belgrade, Belgrade,
Serbia
2
Department of Neurology, Medical University of Innsbruck,
Innsbruck, Austria
some exceptions in the case of late-onset MSA and one Chi-
nese and Korean cohort [4, 7, 8]. By contrast, in European,
American, and Moroccan cohorts, MSA-P was the most
commonly censored phenotype [9–11] [12].
With its variable clinical presentation, MSA represents
a major diagnostic challenge throughout its disease course.
Due to isolated autonomic complaints at prodromal stages,
patients with MSA may refer to other specialists such as
cardiologists or urologists first. When motor symptoms
develop, but are still very mild, MSA may not be distin-
guishable from Parkinson’s disease (PD) or other causes of
sporadic adult-onset cerebellar ataxia (SAOA). Overlapping
features with other atypical parkinsonian disorders, such as
dementia with Lewy bodies (DLB) or progressive supra-
nuclear palsy (PSP), eventually impact on MSA diagnostic
accuracy also at more advanced disease stages [13].
Following Quinn’s effort [14] to rationalize the clini-
cal diagnosis of MSA, consensus conferences were held in
1998 [15] and 2008 [16] to integrate the diagnostic crite-
ria with the latest advances in MSA clinical, pathological,

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and biomarker research. Recent clinicopathological series
highlighted however an overall suboptimal diagnostic accu-
racy, low sensitivity at early disease stages [13, 17, 18], and
other critical issues of the latest MSA criteria set [19], which
eventually prompted the recent revision of MSA diagnostic
criteria endorsed by the International Parkinson and Move-
ment Disorders Society (MDS) [20].
In the present review, we first provide an overview of the
MSA core clinical features, as well as supportive motor and
non-motor features, which should raise a suspicion of MSA
on clinical grounds. Afterwards, we discuss the new set of
MDS MSA diagnostic criteria, with an in-depth focus on
ancillary laboratory findings and strategies to distinguish
MSA from its most frequent look-alikes.
Core Clinical Features of MSA
Autonomic Failure
Up to one-third of patients presenting with isolated auto-
nomic failure [21] may phenoconvert over years into another
central nervous system disorder including MSA [22–24].
Between 5 and 30% of MSA patients may in fact present
with urogenital and cardiovascular autonomic symptoms
several years before any other motor symptom develops
[10, 25, 26].
Bladder function consists of a storage phase, in which
the urethral sphincter is active and the bladder detrusor
inhibited, and a voiding phase, during which the contem-
porary activation of the bladder detrusor and relaxation of
the urethral sphincter favors bladder emptying. Disorders
of neural control of urinary function may result in distur-
bances of the storage phase, such as urinary urge incon-
tinence, and voiding difficulties with interrupted stream
and increased postvoid urinary residual volume. While
disturbances of the storage phase have a major impact on
self-confidence and overall quality of life, voiding difficul-
ties put affected patients at increased risk of urinary tract
infections, hydronephrosis, and secondary kidney failure
[27].
In 73 to 87% of all MSA patients, disturbances of the
storage phase develop early in the disease course due to det-
rusor overactivity and external sphincter weakness [28, 29].
As the disease progresses, sphincter-detrusor dyssynergia
arises, with increasing voiding difficulties, postvoid urinary
residual volume, typically > 100 mL, and recurrent urinary
tract infections [30]. Erectile dysfunction occurs very early
in the disease course and accompanies bladder dysfunction
in virtually all male MSA patients [9, 10]. Questionnaire-
based studies also found reduced genital sensitivity in 47 to
56% of female MSA patients [31, 32]. In both sexes, sexual
dysfunction is due to degenerative changes occurring in the
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The Cerebellum (2023) 22:825–839
spinal sacral region and may precede MSA motor onset by
months or years [10, 33, 34].
Cardiovascular autonomic failure in MSA develops after
neurodegenerative changes of the central autonomic nerv-
ous system (ANS), including brainstem autonomic nuclei
and pre-ganglionic sympathetic fibers to the heart and blood
vessels, and typically results in neurogenic orthostatic hypo-
tension (OH). Neurogenic OH is defined by a sustained sys-
tolic blood pressure fall ≥ 20 mmHg within 3 min of head-up
tilt or active standing, usually accompanied by a diastolic
blood pressure fall ≥ 10 mmHg, which, however, remains
unspecific if isolated [35]. Due to efferent baroreflex dys-
function [36], patients with neurogenic OH typically show
a pathological blood pressure counter-regulation during car-
diovascular autonomic function tests such as the Valsalva
maneuver and, despite severe falls in blood pressure upon
standing, very blunted or sometimes missing compensatory
heart rate increases. An increase in heart rate < 0.5 beats per
minute/mmHg of systolic blood pressure fall after 3 min of
head-up tilt or active standing reliably distinguishes neuro-
genic OH from non-neurogenic causes of OH (sensitivity:
91.3%; specificity: 88.4% for head-up tilt test; sensitivity:
79% for standing test), such as volume depletion or blood
pressure–lowering drugs [37, 38]. At established disease
stages, neurogenic OH occurs in 75 to 81% of MSA patients
[9, 39, 40], with possibly higher frequencies and severity
degrees in the MSA-C than the MSA-P variant [41].
The 2008 MSA diagnostic criteria had introduced higher
cut-off values to diagnose neurogenic OH in the setting of
MSA (≥ 30 mmHg systolic or ≥ 15 mmHg diastolic within
3 min of an orthostatic challenge), but these did not signifi-
cantly improve the specificity for a MSA diagnosis, while
worsening its sensitivity [42]. By contrast, at earlier disease
stages, neurogenic OH may develop beyond the classical
3 min of orthostatic challenge, a phenomenon called delayed
OH. Prolonging the passive or active orthostatic challenge
from 3 to 10 min increases the sensitivity for neurogenic OH
by 18% and it is therefore recommended at the time of the
first diagnostic work-up [43].
Every second person with MSA and neurogenic OH
shows accompanying phenomena, such as postprandial
hypotension [44] and supine and nocturnal hypertension
[45, 46]. While such additional features have major impli-
cations on the disease prognosis [47], their differential diag-
nostic yield remains low due to their high prevalence also
in patients with autonomic failure due to other parkinsonian
disorders [48].
Parkinsonism
Parkinsonism in MSA is usually symmetric, rapidly progres-
sive, and moderately to poorly responsive to L-Dopa. Due
to its axial involvement, patients experience early postural
The Cerebellum (2023) 22:825–839
instability associated with falls. Rapid progression leads to
a shorter latency to disease milestones in MSA; as early as
after 3 years from onset, one-third of patients with MSA
require walking aids, and after 5 years, up to 60% of patients
become wheelchair-bound [1]. Early postural instability is
specific but moderately sensitive for MSA diagnosis [18,
49]. Overall, MSA-C patients have a higher Hoehn and Yahr
stage than MSA-P ones due to unsteadiness caused by cer-
ebellar features [50].
Patients with MSA have in general poorer response
to L-Dopa compared to patients with PD. Poor L-Dopa
responsiveness is defined either by history taking or as less
than 30% improvement on the MDS-UPDRS III on up to
1000 mg L-dopa if needed or tolerated for at least a month.
A retrospective study on a mixed cohort of 100 clinically and
postmortem diagnosed MSA patients reported that, based
on the subjective assessment of the patient or caregiver,
8% had an excellent response to L-Dopa (> 70% benefit),
12% had a good response (50 to 69% benefit), 6% had a
moderate response (30 to 49% benefit), and 74% reported a
poor response to L-Dopa (< 29% benefit) [50]. A proportion
of MSA patients (42 to 57% of MSA-P and 13 to 25% of
MSA-C patients) may initially show a beneficial, but tran-
sient, response to L-Dopa, which diminishes after an aver-
age of 3.5 years [51, 52]. Given that the majority of MSA
patients experience side effects upon L-Dopa administration,
and that an initial poor response may refrain a clinician from
introducing a regular L-Dopa therapy, an acute L-Dopa chal-
lenge test should be avoided in clinical practice [53].
Motor complications include wearing-off fluctuations
in 23%, off-period dystonia in 20%, on–off fluctuations
in 14%, and peak-dose dyskinesia in 11% of moderately
advanced MSA patients [51]. Dyskinesia in patients with
MSA is usually focal, asymmetric, and dystonic affecting
the craniocervical or hands/feet regions; this contrasts with
the generalized choreatic limb dyskinesia typical of patients
with PD [50, 54]. Patients with young-onset MSA more fre-
quently have a good response to L-Dopa, L-Dopa-induced
dyskinesia, and dystonic features compared to patients with
the classic disease onset in the ­6th decade of life [55]. Focal
dystonic postures affecting the face, neck, or limbs prior to
the initiation of L-Dopa were recorded in up to half of MSA
patients, even preceding parkinsonism in some [33].
Cerebellar Syndrome
Cerebellar features, most commonly a broad-based ataxic
gait, occur in 36 to 64% of all MSA patients [9, 25, 26, 33,
39]. Other cerebellar signs encompass limb ataxia (47 to
53% of cases), scanning dysarthria (49 to 69%), and pos-
tural and intention tremor (24 to 56%) as well as cerebellar
oculomotor abnormalities, such as sustained gaze-evoked
horizontal, positional downbeat nystagmus, and saccadic
827
hypermetria (23%) [9, 29, 33, 56]. If considering MSA-C
patients only, gait ataxia is present in virtually all patients,
limb ataxia in 87 to 94%, postural tremor in 45%, and ocu-
lomotor abnormalities in 38 to 41% [9, 10, 29]. Some clini-
cal features, such as the phalanx sign, which is tested with
5 nose-to-examiner’s finger repetitions and indicates limb
dysmetria if the proband’s finger touches the distal inter-
phalangeal joint or beneath, are bedside semiological tools
helpful to distinguish MSA-C from SAOA, when no clear
parkinsonism or autonomic failure is present [57].
Supportive Motor and Non‑motor Features for MSA
Diagnosis
Supportive clinical features, previously termed “red flags,”
include motor and non-motor features suggestive of MSA
that usually become manifest after several years into the dis-
ease course (Table 1). Neuropathological studies showed
that the frequency of such features did not differ in the first
3 years from disease onset between MSA and other parkin-
sonian disorders such as Lewy body disease and PSP, overall
indicating their low diagnostic sensitivity in early disease
stages [13]. However, if a patient develops at least one out of
orofacial dystonia, inspiratory sighs, contractures of hands
or feet, polyminimyoclonus, severe dysarthria, pathologic
laughter or crying, and cold hands and feet, this person is
8.8 times more likely to have MSA-P and 7 times more
likely to have MSA-C than a Lewy body disorder (sensitiv-
ity: 74%, specificity: 88.5%) [13]. If any out of orofacial
dystonia, inspiratory sighs, contractures of hands and feet,
jerky myoclonic postural/action tremor, poliminimyoclonus,
severe dysphonia, and snoring are present, the chance that
this person has MSA-P or MSA-C is respectively 4.3 or 3.1
times higher than PSP (sensitivity for MSA-P: 72.8%, for
MSA-C: 66.7%, specificity: 76.9%) [13].
The European MSA study group applied a checklist
of supportive clinical features for a diagnosis of MSA to
patients with probable MSA-P or PD. Only features with a
specificity > 95% were further categorized into six domains:
early instability, rapid progression, abnormal postures, bul-
bar dysfunction, respiratory dysfunction, and emotional
incontinence. The presence of supportive clinical features
from ≥ 2 categories showed good diagnostic accuracy (sen-
sitivity: 84%, specificity: 98%). If this criterion were applied
to 17 patients with possible MSA-P, 76% of them would
have been correctly diagnosed as probable MSA-P on aver-
age 16 months earlier [59].
MDS Criteria for the Diagnosis of MSA
The new MDS MSA criteria [20] have been developed to
increase the diagnostic accuracy of MSA, particularly in the
early disease stages (Table 1). These criteria include four
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Table 1  MDS criteria for the diagnosis of MSA [20]

Neuropathologically established MSA • Widespread and abundant CNS α-synuclein positive glial cytoplasmic inclusions associated with
neurodegenerative changes in striatonigral or olivopontocerebellar structures [58]
Essential features for clinical MSA diag- • Sporadic, progressive, adult (> 30 years) onset disease
nosis
Clinically established MSA • Autonomic dysfunction defined as at least one of voiding difficulties with postvoid urinary
residual volume > 100 ml, urinary urge incontinence or neurogenic O ­ H& associated with at least
one of poorly L-Dopa-responsive parkinsonism and cerebellar syndrome (≥ 2 ­features*)
• ≥ 2 supportive clinical features
• ≥ 1 brain MRI marker
• Absence of exclusion criteria
Clinically probable MSA • At least two of autonomic dysfunction defined as at least one of voiding difficulties with postvoid
urinary residual volume, urinary urge incontinence or delayed neurogenic O ­ H#, parkinsonism,
and cerebellar syndrome (≥ 1 ­feature*)
• ≥ 1 supportive clinical feature (excluding erectile dysfunction alone)
• Absence of exclusion criteria
Possible prodromal MSA • At least one of polysomnography-proven RBD, delayed neurogenic O ­ H#, and urogenital failure
defined as at least one of erectile dysfunction before age of 60 years with voiding difficulties and
with postvoid urinary residual volume > 100 ml or urinary urge incontinence
• Either subtle cerebellar or subtle parkinsonian signs or both
• Absence of exclusion criteria
Supportive clinical features • Motor features occurring within 3 years from onset such as rapid progression, postural instabil-
ity, severe speech impairment, and severe dysphagia as well as features appearing at any time
during the disease course including craniocervical dystonia induced or exacerbated by L-Dopa in
the absence of limb dyskinesia, unexplained Babinski sign, jerky myoclonic postural or kinetic
tremor, postural deformities
• Non-motor features including stridor, inspiratory sighs, cold discolored hands and feet, erectile
dysfunction and emotional incontinence
Brain MRI markers • For MSA-P: atrophy of putamen, middle cerebellar peduncle, pons and cerebellum, hot cross bun
sign, and increased diffusivity of putamen and middle cerebellar peduncle
• For MSA-C: atrophy of putamen, middle cerebellar peduncle and pons, hot cross bun sign, and
increased diffusivity of putamen
Exclusion criteria • For clinically established and clinically probable MSA: sustained beneficial response to L-Dopa
and unexplained anosmia on olfactory testing
• For possible prodromal MSA: at least one of unexplained anosmia on olfactory testing or abnor-
mal cardiac sympathetic imaging (123I-MIBG-scintigraphy)
• For all clinical categories: typical clinical and brain MRI features of MSA-mimicking conditions
such as PD, DLB, PSP, genetic, and other causes of ataxia
*
Cerebellar features: gait ataxia, limb ataxia, cerebellar dysarthria, and oculomotor features; #delayed neurogenic OH: ≥ 20/10 mmHg blood
pressure drop and ΔHR/ΔSBP ratio < 0.5 bpm/mmHg within 10 min in an upright position; &neurogenic OH: ≥ 20/10 mmHg blood pressure
drop and ΔHR/ΔSBP ratio < 0.5 bpm/mmHg within 3 min in an upright position
bpm beats per minute, CNS central nervous system, DLB dementia with Lewy bodies, HR heart rate, MRI magnetic resonance imaging, MSA-C
MSA-cerebellar type, MSA-P MSA-parkinsonian type, MSA multiple system atrophy, OH orthostatic hypotension, PD Parkinson’s disease, PSP
progressive supranuclear palsy, RBD REM sleep behavior disorder, SBP systolic blood pressure

levels of diagnostic accuracy: neuropathologically estab-
lished MSA, clinically established MSA, clinically probable
MSA, and possible prodromal MSA. Neuropathologically
established MSA is a postmortem-confirmed diagnostic
category, which equals the definite MSA category of the
2008 consensus criteria [16]. The clinically established
MSA category is designed to secure maximum specificity,
with acceptable sensitivity, while the clinically probable
MSA category allows for a balanced sensitivity and speci-
ficity. Possible prodromal MSA is a pure research category
designed to capture patients in the prodromal phase of the
disease. Clinical MSA categories are composed of essential
and core clinical features, supportive motor and non-motor
features, and absence of exclusion criteria. The presence of
the MSA-specific brain MRI marker is required for the clini-
cally established category only, while the clinically probable
category is based exclusively on clinical features. The diag-
nostic accuracy of the MDS MSA criteria will be verified in
a prospective clinical multicenter study.
Essential features for a diagnosis of MSA include an onset
after the age of 30 years, a progressive course, and a nega-
tive family history. The former division into the MSA-P and
MSA-C categories has been retained. Core clinical features
for clinically established MSA and clinically probable MSA
include cardiovascular or urogenital autonomic failure, par-
kinsonism, and cerebellar ataxia stratified according to their

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diagnostic yield into one of the two categories. Specific but
moderately sensitive clinical features are a benchmark of
clinically established MSA, whereas less specific but more
sensitive features occurring usually earlier in the disease
course define the clinically probable MSA category. Unex-
plained voiding difficulties with postvoid residual urinary
volume > 100 ml are necessary for the diagnosis of clinically
established MSA, while the finding of postvoid residual uri-
nary volume < 100 ml is sufficient for the diagnosis of clini-
cally probable MSA. L-Dopa-unresponsive parkinsonism is
required for the diagnosis of clinically established MSA,
but a patient with a good or moderate response to L-Dopa
may be still diagnosed with clinically probable MSA. At
least two cerebellar features are required for a diagnosis of
clinically established MSA, yet a single feature is required
for clinically probable MSA. At least two supportive clini-
cal (either motor or non-motor) features are necessary for
diagnosing clinically established MSA, and only one for
clinically probable MSA (excluding isolated erectile dys-
function). Autonomic failure is mandatory for the diagnosis
of clinically established MSA, whereas any combination of
two out of three core clinical features including that of the
cerebellar syndrome and parkinsonism without autonomic
failure allows for the diagnosis of clinically probable MSA.
Exclusion criteria for clinically established and clinically
probable MSA include the presence of sustained beneficial
response to L-Dopa, unexplained anosmia on olfactory test-
ing, and typical clinical and brain MRI features of MSA-
mimicking conditions such as PD, DLB, PSP, genetic, or
other causes of ataxia.
The possible prodromal MSA category is devised to
diagnose patients at the earliest stages of the disease, when
non-motor symptoms are predominant and associated with
only mild motor symptoms. This category in particular
needs validation in future studies. The entry criteria for this
category are polysomnography-proven REM sleep behav-
ior disorder (RBD), delayed neurogenic OH within 10 min
in the orthostatic position, and urogenital dysfunction. In
an attempt to distinguish patients with possible prodromal
MSA from patients with prodromal PD, an absence of either
unexplained anosmia on olfactory testing or abnormal car-
diac sympathetic imaging (123I-MIBG-scintigraphy) or both
is required. Other exclusion criteria for this category are
essentially the same as for other clinical categories.
Supportive Laboratory Findings for MSA Diagnosis
Although the diagnosis of MSA remains primarily a clini-
cal exercise, brain MRI and evaluation of postvoid residual
urinary volume using bladder sonography, in-and-out cath-
eterization, or urodynamics are now required for the clinical
diagnosis of MSA, whereas polysomnography is required
for the diagnosis of possible prodromal MSA, if RBD is
the presenting symptom. Other ancillary investigations as
shown in Table 2 may be helpful to increase the diagnostic
accuracy at early disease stages [20] and often contempo-
rarily identify individual therapeutic needs. However, one
should keep in mind that these investigations are formally
not part of the MDS MSA criteria [20] due to their limited
diagnostic yield, limited availability, and a lack of valida-
tion. Future studies will clarify which additional laboratory
tests yield sufficient accuracy for the MSA diagnosis, which
will justify their inclusion in future revisions of the MSA
diagnostic criteria [20].
At least one MSA-typical finding at 1.5 T or 3 T brain
MRI is required for a clinically established diagnosis of
MSA (Table 1). The diagnostic yield of the different MRI
findings varies depending on the prevalent motor phe-
notype. While structural brain MRI findings show high
specificity for a MSA diagnosis, their sensitivity remains

Table 2  Supportive laboratory markers of MSA diagnosis (modified from [20])

• Brain MRI markers (for possible prodromal MSA only) including atrophy of putamen, MCP, pons and cerebellum, hot cross bun sign, and
increased diffusivity of putamen and MCP
• Normal cardiac sympathetic imaging and (for clinically established and clinically probable MSA only)
• Polysomnography-proven RBD (for clinically established and clinically probable MSA only)
• FDG-PET hypometabolism of putamen, brainstem, and cerebellum for MSA-P and FDG-PET hypometabolism of putamen for MSA-C
• Supine plasma norepinephrine level > 100 pg/ml associated with neurogenic OH measured using high-performance liquid chromatography
with electrochemical detection after 10 min in supine position
• Detrusor hyperactivity with impaired contraction or detrusor sphincter dyssynergia on urodynamic testing
• Abnormal sphincter EMG with manual analysis including late components defined as > 20% of MUPs with duration > 10 ms or the average
duration of MUPs > 10 ms
• α-synuclein oligomers detected in CSF by PMCA or RT-QUIC
• Increased NfL in CSF or plasma detected by ELISA

CSF cerebrospinal fluid, FDG-PET fluorodeoxyglucose-positron emission tomography, MCP middle cerebellar peduncle, MRI magnetic reso-
nance imaging, MSA-C MSA-cerebellar type, MSA-P MSA-parkinsonian type, MSA multiple system atrophy, MSA multiple system atrophy,
MUP motor unit potential, NfL neurofilament light chain, OH orthostatic hypotension, PMCA protein misfolding cyclic amplification, RT-QUIC
real-time quaking-induced conversion

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limited, especially at the early disease stage [20]. On the
other hand, increased putaminal diffusivity shows an overall
high diagnostic accuracy for distinguishing MSA from PD,
and increased diffusivity of the middle cerebellar peduncle
for differentiating MSA from PSP [60]. Diagnostic algo-
rithms based on multimodal MRI approaches that included
observer-independent brain volumetry, diffusion-weighted
imaging, and iron-sensitive sequences recently showed an
excellent accuracy for a MSA diagnosis [60]. Harmoniza-
tion of protocols for MRI execution and analysis will likely
promote their implementation outside of specialized centers
in the future.
Functional neuroimaging studies may be also implemented
in the diagnostic work-up of MSA, even though are not man-
datory for its diagnosis. Phenotype-dependent varying degrees
of the putamen, pons, and cerebellar hypometabolism on brain
FDG-PET are highly suggestive of MSA in patients present-
ing with parkinsonism or sporadic late-onset cerebellar ataxia
[60], even though cerebellar hypometabolism may also occur
in other causes of genetic or acquired cerebellar ataxia.
Cardiac 123I-metaiodobenzilguanidine (MIBG) SPECT
is an instrumental marker of cardiac sympathetic innerva-
tion, and decreased cardiac MIBG uptake indicates degen-
eration of postganglionic sympathetic fibers to the heart.
Studies from different research groups indicated that cardiac
MIBG-SPECT may support the distinction of MSA from
PD, because MSA is characterized by a pre-ganglionic pat-
tern of ANS lesion and normal cardiac MIBG uptake. Nev-
ertheless, heterogeneous patterns of cardiac tracer uptake
may occur in both diseases [61] possibly due to different
spreading patterns of the neurodegenerative process in single
patients [62], limiting the diagnostic yield of cardiac MIBG-
SPECT in differentiating MSA from PD. Drugs interfering
with noradrenaline transport and vesicular storage, concomi-
tant heart disease, and other frequent causes of small fiber
neuropathy may further impact on cardiac MIBG diagnostic
accuracy in clinical practice.
Supine plasma noradrenaline levels derive from noradren-
aline spill-over from sympathetic nerve endings and rep-
resent another “wet” biomarker of postganglionic sympa-
thetic nerve integrity. In patients with MSA, supine plasma
noradrenaline levels are indeed usually normal (> 100 pg/
ml), while in patients with isolated neurogenic OH, who
later phenoconverted to PD or DLB, these were reported
to be low, again consistent with a pre-ganglionic pattern of
ANS lesion in MSA versus a postganglionic one in PD and
DLB [22, 24].
Recent biomarker studies also showed striking differences
between the cerebrospinal fluid (CSF) profiles of patients
with MSA, which is characterized by oligodendroglial accu-
mulation of α-synuclein, versus those of patients with PD
or DLB, both characterized by neuronal accumulation of
α-synuclein in the so-called Lewy bodies. Increased CSF
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levels of neurofilament light chain > 1.400 pg/ml accu-
rately distinguish MSA from Lewy body disorders (either
PD or DLB) already at prodromal disease stages, in which
patients may present with otherwise undistinguishable iso-
lated autonomic failure [53, 63, 64]. At protein misfolding
cyclic amplification (PMCA) CSF assays, the differences in
α-synuclein strains conformation induce divergent reaction
kinetics, with a faster aggregation rate, but overall lower
maximum Thioflavin T fluorescence in patients with MSA
compared to those with Lewy body disorders, ultimately
enabling an accurate distinction between oligodendroglial
and neuronal α-synucleinopathies both at established and
prodromal disease stages [63, 64].
At the fiberoptic evaluation of swallowing (FEES), more
than 90% of patients with MSA display various degrees of
laryngeal motion abnormalities, which are otherwise only
seldom observed in the setting of PD. FEES findings, whose
diagnostic accuracy for MSA diagnosis is being further
investigated in a multicenter initiative of the MDS MSA
Study group, also provide important information for the
therapeutic management of dysphagia and stridor, which
often complicate advanced MSA stages.
In order to facilitate the standardization of MSA diagno-
sis also outside of referral centers, the criteria to diagnose
urogenital autonomic failure purposely rely on clinical signs
and widely available investigations such as ultrasonography
or in-and-out catheterization to determine the postvoid resid-
ual urinary volume. Urodynamic, and in some cases video-
urodynamic testing, is however the gold standard to separate
neurogenic from non-neurogenic causes of lower urinary
tract dysfunction, and to identify MSA peculiar patterns,
such as insufficient bladder neck tone or detrusor-sphincter
dyssynergia, and tailor the therapeutic approach [27]. Exter-
nal anal sphincter denervation at concentric needle electro-
myography reflects neurodegenerative changes in the sacral
Onuf’s nucleus and also points towards a MSA rather than
PD diagnosis, if documented early in the disease course [65].
Similar findings may be however observed in patients with
PSP or advanced PD as well [66].
Differential Diagnosis of MSA
Overlapping features of MSA and disorders mimicking MSA
that present with autonomic failure, parkinsonism, and cer-
ebellar syndrome result in a common misdiagnosis, par-
ticularly in early disease stages. Based on the predominant
phenotype, differential diagnoses must be considered in the
clinical diagnostic work-up.
Disorders Presenting with Autonomic Failure
Early onset of autonomic failure distinguishes MSA from
PD, in which autonomic failure typically develops at more
The Cerebellum (2023) 22:825–839
advanced disease stages [67], and other causes of acquired or
inherited cerebellar ataxia that usually display milder forms of
autonomic failure, if any [68, 69]. At established disease, the
presence of severe and widespread autonomic failure is a core
clinical feature of MSA and ultimately differentiates it from
other atypical parkinsonian disorders, such as PSP and cor-
ticobasal degeneration, for which severe multi-domain auto-
nomic failure represents an exclusion criterion [70–73]. The
presence of urinary retention is highly specific of MSA versus
PD [41], but less accurate in distinguishing MSA from PSP, in
which neurogenic bladder disturbances may also develop [74].
A number of disorders presenting with autonomic failure
need to be ruled out for the diagnosis of MSA. The most
common cause of peripheral autonomic neuropathy world-
wide is diabetes, followed by kidney and liver disorders,
amyloidosis, infectious (HIV), and paraneoplastic and auto-
immune disorders (such as Sjogren’s syndrome, systemic
lupus erythematosus, rheumatoid arthritis), which all need
to be considered in the differential diagnosis of patients
presenting with isolated autonomic failure. If the origin
of OH is determined to be non-neurogenic, polypharmacy,
dehydration, and anemia need to be sought for. In patients
presenting with a transient loss of consciousness, cardiac
and reflex-mediated syncope, epileptic seizures, and non-
epileptic spells should be ruled out [19].
Previous pelvic surgery, concomitant prostatic hypertro-
phy in men, or pelvic floor prolapse in women may exacer-
bate or mask bladder disturbances of neurogenic origin. In
a series of patients with probable MSA, 43% of males had
undergone futile prostatic or bladder neck surgery before
the correct diagnosis was made [75]. Similarly, other case
series showed that surgery for urinary stress incontinence
gave unsatisfying results in female MSA patients [75, 76].
The diagnostic yield of isolated sexual dysfunction in iden-
tifying patients suffering from incipient MSA remains low
due to the high prevalence of non-neurogenic causes of
sexual dysfunction in the aging population (e.g., endocrine,
vascular). Gastrointestinal disorders as an alternative cause
of dysphagia and constipation need to be excluded as well.
Hypothyroidism may manifest with hypo/anhidrosis and
disordered thermoregulation; cold hands and feet may also
occur in the case of peripheral vascular disorders.
Disorders Presenting with Parkinsonism
Already at symptom onset, patients with MSA show more
severe parkinsonism compared to patients with PD (Hoehn
and Yahr stage > 2 in 54% of MSA and 21% of PD cases)
[77–79]. Although parkinsonian features are often sym-
metric in MSA, around 40% of patients manifest with per-
sisting unilaterality throughout the disease course [17, 29].
Tremor as a presenting symptom is significantly less fre-
quent in MSA (12.5 to 22%) than in PD (60%) [78, 79],
831
and if “atypical” (irregular postural or kinetic and associated
with myoclonic jerk, instead of classic “pill-rolling” tremor)
can be useful for differentiating between the two disorders
[33]. Rapid progression, defined as reaching Hoehn and
Yahr stage ≥ 3 within three years from onset (sensitivity:
69%; specificity: 90%), and early recurrent falls are typical
of MSA compared to PD [78, 80]. In contrast to the monot-
onous and hypophonic speech (hypokinetic dysarthria) of
patients with PD, patients with MSA often manifest a slur-
ring cerebellar dysarthria or a quivering, strained, croaky, or
high-pitched quality voice defined as a mixed dysarthria of
hypokinetic-ataxic-spastic type [50, 81]. If by assigning one
point each for the presence of postural instability, neurogenic
OH, symptoms of overactive bladder, or urinary retention in
the first 2 years from symptom onset, a cumulative score ≥ 2
is reached, MSA may be distinguished from PD with 78%
sensitivity and 86% specificity [67].
Clinical features that argue against MSA diagnosis are sus-
tained L-Dopa response or motor fluctuations with marked
peak-dose appendicular dyskinesia after 5 years from disease
onset, anosmia, hallucinations, and dementia [82–84]. A
small proportion of MSA patients has an excellent response
to L-Dopa and may develop sustained PD-like choreatic peak-
dose dyskinesia closely resembling PD, which led to a non-
beneficial DBS surgery in one study [85]. The absence of overt
autonomic features after 5 years from motor onset strongly
argues against a diagnosis of MSA. However, long-duration
MSA cases with initial parkinsonian features and very late
onset of cardiovascular autonomic failure and bladder prob-
lems (after a mean of 11 years) have been reported [86].
Supranuclear vertical downward gaze paresis is highly
specific for PSP, but mild reductions in downward (6 to 9%)
and upward gaze (20 to 40%) were observed in neuropatho-
logically established MSA cases too [50, 87, 88]. Marked
frontal lobe dysfunction with behavioral abnormalities is
typical for PSP, whereas in MSA, it usually takes the form of
mild executive impairment [83]. Falls in patients with MSA
typically occur after a median of 2 years from motor onset,
which is later compared to patients with PSP, who manifest
with recurrent falls backward starting already in the first year
from onset [80, 89]. However, 28% of MSA patients also
develop falls within the first year from symptom onset [90].
The leading cause of misdiagnosis MSA in patients with
PSP is the presence of cerebellar ataxia. Apraxia, cortical
sensory loss, and aphasia are pathognomonic for corticoba-
sal syndrome and have not been described in postmortem-
confirmed MSA cases [91].
Time course of cognitive impairment plays a major role
in the differential diagnosis of MSA: patients at early stages
of MSA never have dementia, while in early DLB, dementia
is a core feature. At later stages, both disorders may feature
significant cognitive deficits, but these are usually more com-
mon and more severe in patients with DLB [92]. Similarly,
13
832 The Cerebellum (2023) 22:825–839

visual hallucinations do not occur in early MSA and other-
wise seldom throughout the disease course (reported overall
in 9% of MSA). Fluctuating cognition and profound vari-
ations in attention and alertness not related to neurogenic
OH are also uncommon in MSA and rather point towards a
DLB diagnosis. DLB was the most common misdiagnosis in
a clinicopathological study of patients diagnosed antemor-
tem with MSA and the confounding element was in fact the
presence of severe autonomic failure in these patients [17]. A
provisional algorithm featuring some of the diagnostic tools
relevant to the differential diagnosis of a patient with parkin-
sonism unresponsive to L-Dopa is given in Fig. 1.
Disorders Presenting with Cerebellar Syndrome
In a patient with suspected MSA-C, SAOA as well as symp-
tomatic, genetic, and immune-mediated ataxia needs to be
ruled out.
Symptomatic ataxia due to brain mass lesions and menin-
geal infiltrates, multiple sclerosis, toxic substances and med-
ications (alcohol, carbamazepine, phenytoin, lithium), HIV,
and metabolic disbalance (B1 and B12 deficiency, hypothy-
roidism) should be considered in patients with a subacute
onset of ataxia over weeks or months.
A major differential diagnostic challenge in patients with
suspected MSA-C is SAOA, defined as a progressive ataxia
with onset after 40 years of age, with negative family his-
tory and no established cause of acquired ataxia based on
clinical, imaging, and laboratory findings [93]. Patients with
SAOA usually manifest additional non-ataxia features such
as pyramidal signs and mild urinary dysfunction resembling
that of MSA-C. Diagnosis of SAOA is made by exclusion,
but a slower progression rate, milder cerebellar features, as
well as absence of severe autonomic failure, RBD, and MRI
markers suggestive of MSA-C are helpful diagnostic clues
[94]. A proportion of patients with MSA-C, who manifest

Fig. 1  Diagnostic algorithm

for a patient suspected of MSA Parkinsonism suspected of
MSA (levodopa unresponsive)
with adult-onset progressive
parkinsonism unresponsive to
L-Dopa
Conventional
MRI

Atrophy of putamen, MCP, pons and Atrophy of midbrain, SCP and

Normal cerebellum, hot cross bun sign and putamen and ↑ diffusivity of
↑ diffusivity of putamen and MCP putamen and SCP

Bladder sonography of MSA PSP

urodynamics

Postvoid residual urine, detrusor Normal or

underactivity, detrusor-sphincter detrusor
dyssynergia, open bladder neck overactivity

MIBG
MSA scintigraphy Smell test

Abnormal* Normal Hypo/ansomia Normal

Neuropsychological
FDG-PET PD vPSG
tests

Normal cognition of Hypometabolism in Hypometabolism in

Dementia mild cognitive putamen, pons and/or midbrain and cortical Normal RBD Normal
impairment cerebellum regions

Absence of nigral Absence of nigral Nigral

PDD or DLB PD hyperechogenicity on hyperechogenicity on hyperechogenicity on MSA PSP
TCS TCS TCS

MSA PSP PD

*Abnormal = cardiac sympathec denervaon; DLB = demena with Lewy bodies; MIBG-Spect = 123I-
metaiodobenzylguanidine scingraphy; MSA = mulple system atrophy; PD = Parkinson’sdisease;
PDD = Parkinson’s disease demena, PSP = progressive supranuclear palsy; RBD = REM sleep behavior
disorder; TCS = transcranial sonography; vPSG = video-polysomnography

13
The Cerebellum (2023) 22:825–839 833

Ataxia suspected of MSA

Conventional MRI

Normal or isolated cerebellar Pontine, MCP and putaminal

atrophy atrophy

Exclude meningeal
infiltrations, metabolic,
MSA
infectious, toxic, and immune
mediated causes

Screening for mutations in

ATXN1, ATXN2, ATXN3,
CACNA1A, ATXN7, PPP2R2B,
FMR1, TBP, RFC1, FXN and
ATN1 genes

Negative

Tilt table test and/or urinary

function testing and/or vPSG
and/or DAT-Spect

Abnormal* Normal

MSA SAOA

*Abnormal = neurogenic OH, postvoid urine retenon, REM sleep behavior disorder and apresynapc
nigrostriatal dopaminergic denervaon; MCP = middle cerebellar peduncle; MSA = mulple system
atrophy; SAOA = sporadic adult onset ataxia; vPSG = video-polysomnography

Fig. 2  Diagnostic algorithm for distinguishing MSA-C from SAOA

with isolated ataxia at disease beginning and develop auto-
nomic failure only years later may be initially misdiagnosed
with SAOA [93]. In the clinical series, the sensitivity of
neurogenic OH for distinguishing MSA-C from SAOA at
early disease was 32 to 56%; the specificity was 94 to 100%.
In more advanced diseases, neurogenic OH sensitivity for
MSA-C versus SAOA raised to 64 to 73%, and specificity to
100% [95, 96]. Given that 20% of patients with SAOA may
harbor a pathogenic mutation, genetic screening for the most
common causes of inherited ataxia in the referral population
is required [94].
Positive family history, earlier onset, and slower progres-
sion point towards genetic ataxia, in particular autosomal
dominant cerebellar ataxia, since patients with autosomal
recessive cerebellar ataxia with symptom onset in adulthood
usually have a negative family history [97]. Genetic screen-
ing should be therefore performed in selected cases with
positive family history, early onset (i.e., in the ­4th decade
of life or earlier), presence of clinical features atypical for
MSA (i.e., retinitis pigmentosa suggestive of SCA7 or ves-
tibular neuropathy suggestive of CANVAS), and absence of
typical MSA features (i.e., severe and progressive autonomic

13
834
failure). As mentioned above, genetic testing should be
tailored according to the relative frequency of different
mutations in the referral population. In European natives,
pathogenic mutations should be searched in genes produc-
ing SCA1 (ATXN1), SCA2 (ATXN2), SCA3 (ATXN3), SCA6
(CACNA1A), SCA7 (ATXN7), SCA 12 (PPP2R2B), fragile
X tremor ataxia syndrome (FMR1), SCA17 (TBP), CAN-
VAS syndrome (RFC1), and Friedreich ataxia (FXN) [53]. In
Japanese natives, screening for mutations in the CoQ2 gene
should be additionally performed in patients with positive
family history [98], as this is the only mutation known to
produce MSA. Selected patients with a complex phenotype
of movement disorders, dementia, and psychiatric symptoms
may be screened for DRPLA (ATN1) [53].
Immune-mediated ataxia disorders include paraneoplastic
cerebellar degeneration (associated with anti-Yo, anti-Hu,
anti-Ri, and other specific antibodies), gluten ataxia associ-
ated with anti-transglutaminase-6 antibodies, postinfectious
cerebellitis, and primary autoimmune cerebellar ataxia, in
which an autoimmune origin is suspected, but there is lack
of an obvious trigger or an unclear association with antibod-
ies. This condition may be often misdiagnosed as SAOA
[99]. These potentially treatable MSA-C mimics have a
subacute onset and rapid progression, and may sometimes
be presented with additional clinical features suggestive of
underlying malignancy or gluten sensitivity. Other antibody-
associated disorders (such as anti-CASPR2, anti-CRMP5,
anti-Homer3) may present with cerebellar features, RBD,
autonomic dysfunction, and hot cross bun sign [100].
A diagnostic algorithm employing various laboratory tools
for distinguishing MSA-C from SAOA is provided in Fig. 2.
Differential Diagnosis in Prodromal Stages
The diagnostic criteria for prodromal PD [101], DLB [102],
and MSA [20] have been recently published and their vali-
dation for use in the clinical routine and clinical trials is
currently pending. These criteria are designed to identify
patients at the earliest disease stage based on the presence
of early clinical features.
RBD is a universal prodromal marker of synucleinopa-
thy. A clinically suspect or eventually a polysomnogra-
phy-proven diagnosis of RBD does not therefore help
to differentiate MSA from other α-synucleinopathies,
but eventually supports their identification at prodromal
disease stages, and the distinction of MSA-P from PSP
or corticobasal degeneration and of MSA-C from other
causes of cerebellar ataxia [19]. Among prodromal risk
factors for PD, polysomnography-proven RBD carries the
greatest risk [likelihood ratio (LR) = 130], followed by
abnormal dopaminergic PET/SPECT (LR = 43.3), subtle
motor signs (LR = 10), and neurogenic OH (LR = 18.5)
13
The Cerebellum (2023) 22:825–839
[103]. Since both polysomnography-proven RBD and
autonomic failure are entry criteria for a diagnosis of pos-
sible prodromal MSA diagnosis if associated with mild
motor signs, the absence of at least one out of anosmia or
denervation on cardiac sympathetic imaging, which would
otherwise point towards a future phenoconversion to PD,
is required [20].
More recently, isolated autonomic failure has been also
identified as another prodromal marker of synucleinopathies
[21]. Patients with isolated autonomic failure may pheno-
convert to MSA, PD, or DLB, and several clinical and labo-
ratory markers have been recently identified as predictors
of future phenoconversion to MSA instead of Lewy body
disorders including younger age at onset, preserved olfac-
tion, supine heart rate > 70 bpm associated with supine
plasma norepinephrine > 100 pg/ml, and orthostatic HR
increase > 10 bpm after 3 min [104].
In contrast, criteria for prodromal DLB target the pre-
dementia stage and define mild cognitive impairment, delirium,
and psychiatric-onset presentations. Although among patients
with isolated autonomic failure who later phenoconverted to
an α-synucleinopathy with central nervous system involve-
ment, 52% progressed to DLB [104], this presentation was not
deemed sufficiently specific to be included in the criteria for
prodromal DLB. However, in the context of transition from
mild cognitive impairment to dementia, patients who present
with parkinsonism and autonomic failure are more likely to be
diagnosed with DLB than with other types of dementia [102].
Conclusion
For a relentlessly progressive disease with no cure such as
MSA, an early and correct diagnosis is of paramount impor-
tance for a personalized care and timely enrollment into
clinical trials with disease-modifying candidate drugs. At
the moment, the diagnosis of MSA is still based on clinical
grounds despite recent developments in laboratory markers,
for which validation in large clinical studies is needed. The
new MDS MSA criteria are devised to help an earlier and
more accurate diagnosis of MSA, since the certainty of the
previous criteria sets was suboptimal. For the first time, the
category of possible prodromal MSA is outlined to assist in
identifying patients at the earliest stages who might progress
to MSA, and who therefore require a close follow-up. The
validation exercise on the MDS MSA criteria is currently
underway by the MDS MSA Study Group. Future studies
should aim for a better characterization of MSA patients
by collecting more detailed prospective clinical and labora-
tory data, including novel imaging techniques (such as the
recently announced α-synuclein functional imaging) with
postmortem diagnostic confirmation.
The Cerebellum (2023) 22:825–839
Funding Open access funding provided by University of Innsbruck
and Medical University of Innsbruck. Academic work without external
financial support.
Declarations
Conflict of Interest Full financial disclosures for the past 12 months:
Iva Stankovic: Dr. Stankovic has nothing to disclose.
Alessandra Fanciulli: Dr. Fanciulli reports royalties from Springer Na-
ture Publishing Group, speaker fees and honoraria from International
Parkinson Disease and Movement Disorders Society, Austrian Neurol-
ogy Society, Austrian Autonomic Society, Abbvie, and Theravance
Biopharma, and research grants from the Stichting ParkinsonFond, US
MSA Coalition, Dr. Johannes Tuba Stiftung and the Österreichischer
Austausch Dienst, outside of the submitted work.
Victoria Sidoroff: Dr. Sidoroff has nothing to disclose.
Gregor K. Wenning: Dr. Wenning reports speaker honoraria from Bio-
haven, Biogen, Inhibikase, Lundbeck, Ono, Takeda, and Theravance.
Open Access This article is licensed under a Creative Commons Attri-
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