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Multiple system atrophy: Clinical features and diagnosis

Multiple system atrophy: Clinical features and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Jan 17, 2024.

INTRODUCTION — Multiple system atrophy (MSA) is rare neurodegenerative disorder that encompasses autonomic, pyramidal, parkinsonian, and cerebellar features. It is one of several neurodegenerative disorders associated with alpha-synuclein aggregation, or synucleinopathies; others include Parkinson disease (PD) and dementia with Lewy bodies (DLB).

MSA is important to consider in older adults with progressive autonomic and motor dysfunction. It is referred to as an atypical parkinsonian disorder based on distinct yet overlapping features with PD; other atypical parkinsonian disorders include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

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

CLINICAL FEATURES — The core clinical features of MSA, which occur in varying combinations, are parkinsonism (bradykinesia plus rigidity and/or tremor), autonomic failure, cerebellar ataxia, and pyramidal signs. The onset of disease can be marked by any characteristic motor or autonomic feature [1].

Age of onset — MSA is an adult-onset neurodegenerative disorder. The mean age of onset is 54 to 58 years [2-4], which is younger than that seen in Parkinson disease (PD). Pathologically confirmed cases have been described with an onset as young as 31 years and as old as 78 years [3]. Parkinsonian and cerebellar subtypes have a similar age of onset [4]. (See 'Motor involvement' below.)

Prodromal symptoms — In retrospect, patients diagnosed with MSA can at times identify symptoms that began years before the clinical diagnosis was evident. Such early signs and symptoms are seen as a possible window of opportunity for disease-modifying and preventive strategies targeting alpha-synuclein as well as other pathways.

Three main features have received the most interest as prodromal symptoms of MSA:

Rapid eye movement sleep behavior disorder – Among patients with isolated rapid eye movement (REM) sleep behavior disorder (RBD) who are followed longitudinally and eventually develop a neurodegenerative disorder, approximately 5 to 10 percent have MSA [5,6]; most of the remaining 90 percent have either PD or dementia with Lewy bodies (DLB). RBD can emerge up to two decades before clinical motor symptoms are observed. Risk factors for neurodegeneration in patients with RBD are discussed in detail separately. (See "Rapid eye movement sleep behavior disorder", section on 'Risk of neurodegenerative disease'.)

Isolated autonomic failure – Autonomic dysfunction, especially involving the lower urinary tract (eg, urinary incontinence), is a common early symptom of MSA, sometimes preceding all other diagnostic features. In one longitudinal series of patients diagnosed with MSA and queried about early symptoms, initial urinary symptoms were the sole initial manifestation of MSA in 18 percent of patients, occurring at a mean of 2.8 years before motor signs developed [7].

Pure autonomic failure (PAF) or idiopathic orthostatic hypotension, like RBD, is increasingly recognized as a risk factor for future synucleinopathy, with a phenoconversion rate of 12 to 35 percent in various studies with variable follow-up [8-11]. In a series of 275 patients with PAF followed at a tertiary care clinic, 24 percent were eventually diagnosed with a synucleinopathy, most commonly MSA (51 percent) [8]. The median time to conversion to MSA was 5.9 years. Patients eventually diagnosed with MSA tend to be younger and have more severe bladder symptoms as compared with those with PD or DLB.

Subtle motor signs – Mild parkinsonian signs, especially if symmetric and without tremor, or cerebellar dysfunction that are insufficient to diagnose clinical disease may be present prior to the onset of other disease-defining features. Such features are usually nonspecific, particularly in the absence of other features such as autonomic dysfunction. In patients with subtle or equivocal motor signs and RBD, the presence of hyposmia may point towards a diagnosis of a synucleinopathy, although the severity of hyposmia tends to be lower in MSA than in PD or DLB. In some patients with MSA, the sense of smell may be normal.

In some cases, it may be possible for patients to participate in clinical trials based on isolated symptoms that do not fulfill criteria for clinical disease but that may indicate increased risk for future phenoconversion to MSA or other synucleinopathies. One resource for patients is the North American Prodromal Synucleinopathy (NAPS) Consortium. Research criteria for possible prodromal MSA have been proposed [12]. (See 'Possible prodromal MSA (research only)' below.)

Motor involvement — The motor manifestations of MSA are classified clinically into two separate but overlapping subtypes [13-15]:

MSA with predominant parkinsonism (MSA-P)

MSA with predominant cerebellar ataxia (MSA-C)

In most studies from Europe and North America, cases of MSA-P outnumber MSA-C by between two and four to one [2,16]. This contrasts with studies from Japan, which report MSA-C as more common than MSA-P [17].

The predominant motor feature can change over time with disease progression [18]. Thus, the designation of MSA-P or MSA-C refers to the predominant motor problem at the time the patient is evaluated.

Parkinsonism (MSA-P) — 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 jerky postural tremor involving the arms, which has also been referred to as minipolymyoclonus [19]. Up to one-third of patients with MSA-P also have a mild rest tremor [20,21]. 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 [14,17].

Additional movement disorders associated with MSA-P may include stimulus-sensitive cortical myoclonus, hemiballism and chorea, and dystonia unrelated to dopaminergic therapy [22-24]. 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).

Cerebellar dysfunction (MSA-C) — 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 [14]. Ocular abnormalities may include gaze-evoked nystagmus, impaired smooth pursuits with saccadic intrusion, and/or ocular dysmetria.

Speech and swallowing — Dysphagia is a prominent symptom of both clinical subtypes of MSA [25].

The speech pattern of patients with MSA is characteristic. In addition to the hypophonic monotony often seen in PD, patients with MSA-P also have an increase in pitch and a quivering, strained element to their speech [14]. By contrast, patients with MSA-C have a more typical cerebellar scanning dysarthria.

Postural abnormalities — Camptocormia (severe anterior flexion of the spine) (figure 1) and disproportionate antecollis (figure 2) are common abnormalities of posture in MSA [14,26]. The anterocollis, in particular, is characteristic of MSA, although it can occur in other forms of degenerative parkinsonism [27-29].

These postural abnormalities may be the result of axial dystonia, myopathy, or perhaps both [30-32]. Some have hypothesized that dystonia is the initial feature and that myopathy appears later due to muscle damage. There are no longitudinal data to support this possibility, however.

Dysautonomia — Dysautonomia is a feature of both parkinsonian and cerebellar MSA presentations [14]. Among patients in a large European MSA registry, symptomatic dysautonomia was present in almost all patients, with high rates of urinary dysfunction (83 percent) and symptomatic orthostatic hypotension (75 percent) [2].

Urinary dysfunction – 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) [33]. Although these features are also seen in PD, they generally begin earlier and are more profound in MSA [34].

Urodynamic studies in patients with MSA commonly show impaired detrusor contractility and detrusor-sphincter dyssynergia. In a study of 52 patients with MSA who had undergone urodynamic analysis, detrusor underactivity with dysuria was observed within four years of disease onset in 58 percent of patients and thereafter in 76 percent [35]. Other common findings in MSA include bladder neck incompetence and external sphincter denervation.

Postvoid residual (PVR) volumes are often measurable in patients with MSA, indicating some degree of impaired detrusor function, if not frank urinary retention. In longitudinal studies, PVR increases over time in patients with MSA. A significantly elevated PVR (eg, >100 mL) distinguishes patients with MSA from those with PD with high specificity but is not useful in the distinction between MSA and progressive supranuclear palsy (PSP) [12]. Approximately 14 percent of patients with MSA require self-catheterization by five years [36]. A smaller subgroup of patients with probable MSA have urinary retention requiring catheterization at the time of diagnosis [37].

Erectile dysfunction – Nearly all males with MSA have erectile dysfunction, which is usually an early symptom [14].

Orthostatic hypotension – In the natural history of MSA, neurogenic orthostatic hypotension usually emerges after urogenital symptoms appear. In a cross-sectional study of 100 patients with MSA, symptomatic orthostatic hypotension was present in 68 percent and was severe in 15 percent [15]. For the purposes of the diagnostic criteria for MSA, orthostatic hypotension is defined as a drop of 20 mmHg or more in systolic blood pressure within 10 minutes of standing. Patients will usually but not always have a corresponding drop in diastolic blood pressure of ≥10 mmHg and a lack of compensatory increase in heart rate (in the absence of beta blockers or other medications that may blunt the heart rate response). (See 'Diagnostic criteria' below.)

Anhydrosis – Up to 80 percent of patients have decreased sweating, including nearly half with anhydrosis [38].

Constipation – Constipation is a common symptom of autonomic dysfunction in patients with MSA. Electromyography of the external anal sphincter may show chronic reinnervation with markedly prolonged motor units [39-41]. Such changes are supportive of MSA but not specific; similar changes can be seen in PD as well as with cauda equina injury and following pelvic or obstetric surgery or injury [12,42].

Nonmotor features

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 (2 percent) [43].

At least two-thirds of patients have RBD [44,45]. 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 [5,46]. Patients with early RBD may be more likely to have an autonomic onset of MSA and less likely to manifest parkinsonism [45]. RBD tends to decrease in severity as the disease progresses [16]. (See "Rapid eye movement sleep behavior disorder".)

Nocturnal or diurnal laryngeal stridor occurs in approximately 15 to 40 percent of patients with MSA [47]. It is a fairly specific feature of MSA, which is uncommon in PD and other neurodegenerative disorders [16]. Stridor is caused by laryngospasm with impaired vocal cord abduction and/or paradoxical adduction. 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 [48], 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 PD [49].

Cognitive function — Cognitive function in MSA tends to be relatively preserved compared with PD and other atypical parkinsonian disorders, possibly reflecting a lesser degree of cortical involvement in MSA [50] 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 PD and PSP [51]. 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 proven 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.

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 PSP. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis", section on 'Cognitive and behavioral abnormalities'.)

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 [52,53]. In one study of 286 patients with MSA, probable depression and probable anxiety were present in 43 and 37 percent, respectively [52].

Olfactory dysfunction is generally mild in MSA [54]; a small case-control study found that olfactory dysfunction in MSA is less severe than that seen in PD [55].

Exclusionary features — A variety of "red flag" or exclusionary features can help to distinguish MSA from other parkinsonian disorders. These features occasionally occur in patients with pathologically confirmed MSA, particularly late in the disease, and the presence of a single feature does not exclude the diagnosis. However, the presence of any of these findings at the time of presentation should signal that an alternative diagnosis may be more likely.

For the purposes of the formal diagnostic criteria for MSA, exclusionary features include the following [12]:

Substantial and persistent beneficial response to dopaminergic medications (see 'Levodopa response assessment' below)

Anosmia (severe loss of olfaction) on olfactory testing (not explained by other common causes such as allergic rhinitis, smoking, structural nasal lesions, or nasal surgery)

Abnormal cardiac sympathetic imaging (123I-metaiodobenzylguanidine [MIBG, iobenguane]-scintigraphy)

Fluctuating cognition with early decline in visuoperceptual abilities

Recurrent visual hallucinations (not secondary to medications) within three years of disease onset

Dementia (table 1) within three years of disease onset

Downgaze supranuclear palsy (more suggestive of PSP)

Brain magnetic resonance imaging (MRI) findings suggestive of an alternative diagnosis

An alternative condition known to produce autonomic failure, ataxia, or parkinsonism and plausibly connected to the patient's symptoms

Neuroimaging — Common MRI findings in patients with MSA include (image 1 and image 2) [18,56-58]:

Atrophy of the putamen, pons, middle cerebellar peduncles, and cerebellum

T2 hypointensity of the posterior putamen (also described as a slit-like void), T2 hyperintensity in the lateral putaminal rim ("putaminal rim sign"), and T2 hyperintensities of the middle cerebellar peduncles

"Hot cross bun" sign, referring to hyperintense T2 signal in the shape of a cross within the pons that arises from degeneration of transverse pontocerebellar fibers

Increased diffusivity (high apparent diffuse coefficient [ADC] values) in the putamen and middle cerebellar peduncles

These changes are supportive of the diagnosis of MSA rather than PD. However, they are not necessarily present in all patients with MSA, particularly early in the disease. In addition, these signs are not specific for differentiating MSA from other atypical parkinsonian disorders, including PSP [56]. Even the "hot cross bun" sign is not specific and can be seen in patients with other causes of parkinsonism and ataxia [58-60].

Compared with visual inspection of individual patient MRIs, quantitative comparisons of atrophy and diffusivity patterns among groups of patients with MSA versus other parkinsonian disorders reveal differences that may eventually prove useful in the clinic. In one systematic review, putaminal diffusivity had high sensitivity and specificity (90 and 93 percent) for distinguishing between patients with MSA-P and PD [61]. Preliminary data suggest that this technique can also be used to monitor disease progression in MSA [62].

Positron emission tomography using 18-F fluorodeoxyglucose (FDG-PET) in patients with MSA may reveal regional glucose hypometabolism in the striatum, brainstem, and cerebellum, similar to atrophy patterns visualized on structural MRI. However, similar to MRI, the sensitivity and specificity of these findings for differentiating MSA from PD remain uncertain [56].

Striatal dopamine transporter imaging using single-photon emission computed tomography (SPECT; eg, 123I-FP-CIT SPECT scan or DaTscan) is typically abnormal in patients with MSA, as it is in patients with PD and other parkinsonian disorders. An abnormal result may be most useful clinically in patients with predominant ataxia, to help distinguish MSA from other causes of adult-onset ataxia. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan'.)

Other biomarkers — No positive biomarkers of MSA have yet emerged whose presence points specifically to a clinicopathologic diagnosis of MSA. In some cases, however, the absence of a finding (or a normal result) helps to point towards an alternative diagnosis.

One example is 123I-MIBG imaging of the heart, which demonstrates postganglionic abnormalities in patients with PD but not those with MSA [63,64]. This cardiac imaging technique shows promise for differentiating the two diseases, but its clinical utility has yet to be established. Reduced sympathetic innervation can occur due to nondegenerative etiologies as well, including medication effects, structural heart disease, and diabetic small fiber neuropathy.

Another potential approach is the use of skin biopsy. Peripheral deposition of alpha-synuclein has been identified within cutaneous autonomic nerve fibers seen on skin biopsy tissue, particularly in synucleinopathies including PD, RBD, DLB, PAF, and MSA. This has led to a growing interest in the use of this technique as a minimally invasive diagnostic biomarker. Although skin biopsy test kits are available commercially for clinical use, more longitudinal studies are needed to understand their usefulness in diagnosis. Several studies indicate potential utility in distinguishing between PD and MSA. As examples:

One study included neurologic examination, autonomic testing, and skin biopsies in 31 patients with probable MSA per diagnostic criteria, 54 patients with definite PD per the UK Parkinson’s Disease Society Brain Bank Diagnostic Criteria, and 24 matched controls [65]. Patients with PD had reduced nerve fiber densities compared with patients with MSA and controls. All 31 patients with MSA and 51 of 54 patients with PD had evidence of phosphorylated alpha-synuclein (P-syn) in at least one skin biopsy. No P-syn was detected in controls. Patients with MSA had greater P-syn deposition and more widespread peripheral distribution than patients with PD. PD followed a proximal-distal gradient, while MSA appeared more evenly distributed. A variety of individual metrics and cutoffs were able to distinguish PD from MSA with high sensitivity and specificity on receiver operating characteristic (ROC) curve analyses. Validation on external cohorts has not yet been reported.

Another study compared P-syn staining in skin biopsies of 25 patients with MSA-P and 25 patients with PD with orthostatic hypotension (PD-OH) [66]. Biopsies from patients with MSA-P mainly showed somatic (epidermal) fiber involvement with relatively preserved autonomic innervation; by contrast, PD-OH biopsies displayed prevalent abnormal P-syn deposits and denervation in autonomic postganglionic nerves. This study did not show the similar proximal-distal gradients like the other study, and density of synuclein staining was greater in the PD group.

In a separate technique, seed amplification assays (SAAs; eg, real-time quaking-induced conversion [RT-QuIC] and protein misfolding cyclic amplification [PMCA]) can detect and quantify alpha-synuclein in a variety of tissues, including blood, cerebrospinal fluid, olfactory mucosa, and skin biopsy homogenates. Alpha-synuclein SAAs are able to distinguish patients with synucleinopathies from control subjects and those with non-synuclein neurodegenerative diseases with relatively high sensitivity and specificity but do not perform as well in distinguishing between PD and MSA [67-69].

Other potential biomarkers are being studied but are not widely available or do not have sufficient specificity to be useful clinically [12]. These include alpha-synuclein oligomers in cerebrospinal fluid (CSF), which may be elevated in any of the synucleinopathies; neurofilament light chain levels in plasma and CSF, which may be elevated in patients with MSA but low in patients with PD and DLB; and supine norepinephrine levels in association with orthostatic hypotension, which are relatively preserved (>100 picograms/mL) in patients with MSA but lower in those with PD.

EVALUATION AND DIAGNOSIS — MSA should be suspected in patients with adult-onset, progressive parkinsonism and/or cerebellar dysfunction associated with early or severe dysautonomia. 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.

History and neurologic examination — History and neurologic examination are central to the diagnosis of MSA, both to confirm key clinical features of the disease and to rule out alternative and competing disorders.

Key elements of the history include the nature and timing of first symptoms, ideally with collateral information from family and friends, speed of progression, and impact on function. MSA tends to begin at an earlier age and progress more rapidly than Parkinson disease (PD), with early postural instability and falls and relative sparing of cognition and memory. Patients and bed partners should be asked about dream enactment suggestive of rapid eye movement (REM) sleep behavior disorder (RBD), which they may not volunteer on their own. RBD is common in prodromal and established synucleinopathies and can be a key clue in the differentiation between MSA and nonsynuclein disorders such as progressive supranuclear palsy (PSP) or other causes of ataxia. (See 'Clinical features' above.)

The urologic history includes questions about storage symptoms (urinary urgency, daytime frequency, nocturia, urge incontinence), voiding symptoms (hesitancy, intermittent urinary stream or poor flow, sensation of incomplete bladder emptying), and erectile dysfunction in males. Measurement of the postvoid residual (PVR) volume by ultrasound is useful if available in the clinic. Depending on the comfort level of the neurologist and primary care clinician, patients may need to be referred to urology to evaluate for prostate enlargement or pelvic floor pathology as competing causes of lower urinary tract symptoms. (See "Female urinary incontinence: Evaluation" and "Lower urinary tract symptoms in males", section on 'Lifestyle and behavioral therapy for all patients'.)

Patients should be asked about signs and symptoms of orthostatic hypotension, including episodes of syncope and falls related to lightheadedness, visual blurring, cognitive slowing, leg buckling, and neck pain and headache localized in the suboccipital, posterior cervical, and shoulder region ("coat-hanger sign"). The medication list should be reviewed for causal or contributing medications (table 2). The diagnostic evaluation for orthostatic hypotension is reviewed in detail separately. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Diagnostic evaluation'.)

Levodopa response assessment — Levodopa responsiveness should be tested in all patients with parkinsonism, not only to help distinguish MSA from PD but also for the chance of symptomatic benefit. 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) 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 PD.

In the early stages, MSA with predominant parkinsonism (MSA-P) may be difficult to distinguish from PD [14].

An excellent and sustained response to dopaminergic therapy is an important supportive feature for establishing the diagnosis of PD. (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 [35,70,71]. While open-label and retrospective studies suggest transient benefit from levodopa in 30 to 50 percent of patients with MSA [15,20,35,70-75], 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 [76].

Levodopa responsiveness is tested by administering carbidopa-levodopa in escalating doses up to 1000 mg of levodopa daily as necessary and tolerated over several months [14]. A positive response requires a clinically significant improvement in motor symptoms, defined objectively as a 20 to 30 percent improvement in the motor component of the Unified Parkinson Disease Rating Scale (UPDRS) for at least a month [12].

As in PD, levodopa treatment may trigger or exacerbate orthostatic hypotension in patients with MSA [14]. Levodopa use can also 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) [77]. 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 [78]. Some patients with MSA may develop generalized dyskinesia as seen in PD.

Other testing — Structural MRI should be performed in all patients to exclude findings suggestive of an alternative diagnosis [12]. The basal ganglia, brainstem, and cerebellum should also be inspected for atrophy and T2 signal changes supportive of MSA. (See 'Neuroimaging' above.)

No other testing is required in most patients. Urodynamic studies and tilt table testing can be useful in selected patients to clarify the etiology of symptoms when the history is unclear or uninformative. In-laboratory polysomnography is useful in some patients to evaluate for RBD and sleep-related breathing disorders. (See 'Sleep and breathing disorders' above.)

Exploratory biomarkers are primarily used for research related to possible prodromal MSA. (See 'Other biomarkers' above.)

Diagnostic criteria — The diagnostic criteria for MSA were revised substantially in 2022 to include supportive brain MRI findings as well as proposed research criteria for possible prodromal MSA [12,13,18].

Clinically established MSA — The diagnosis of clinically established MSA during life requires all of the following (table 3) [12]:

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

Autonomic dysfunction defined as (at least one is required):

Unexplained voiding difficulties with PVR volume ≥100 mL

Unexplained urinary urge incontinence

Neurogenic orthostatic hypotension defined by a blood pressure reduction within three minutes of standing by ≥20 mmHg systolic or ≥10 mmHg diastolic

At least one of:

Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability)

Cerebellar syndrome (at least two of gait ataxia, limb ataxia, cerebellar dysarthria, or oculomotor dysfunction)

At least two supportive motor or nonmotor clinical features:

Rapid progression within three years of motor onset

Moderate to severe postural instability within three years of motor onset

Craniocervical dystonia induced or exacerbated by levodopa in the absence of limb dyskinesia

Severe speech impairment within three years of motor onset

Severe dysphagia within three years of motor onset

Unexplained Babinski sign

Jerky myoclonic postural or kinetic tremor (minipolymyoclonus)

Postural deformities

Stridor

Inspiratory sighs

Cold discolored hands and feet

Erectile dysfunction (below age of 60 years for clinically probable)

Pathologic laughter or crying

At least one brain MRI marker (each affected brain region as evidenced by atrophy or increased diffusivity counts as one MRI marker):

For MSA with predominant parkinsonism (MSA-P) – Atrophy of putamen (and signal decrease on iron-sensitive sequences), middle cerebellar peduncle, pons, and/or cerebellum; "hot cross bun" sign; and/or increased diffusivity of putamen and/or middle cerebellar peduncle

For MSA with predominant cerebellar ataxia (MSA-C) – Atrophy of putamen (and signal decrease on iron-sensitive sequences), infratentorial structures (pons and middle cerebellar peduncle); "hot cross bun" sign; and/or increased diffusivity of putamen

Absence of exclusionary features (see 'Exclusionary features' above)

In a study from the Queen Square Brain Bank using post-mortem neuropathologic diagnosis as a gold standard, these criteria had high specificity (100 percent) but low sensitivity (20 percent) when applied early in the disease course (within three years of symptom onset) [79]. Sensitivity improved to 51 percent when applied in the final stages of disease. As expected, sensitivity was higher for clinically probable MSA (62 and 95 percent for early and late time points, respectively), while specificity remained high (>90 percent). Other autopsy validation studies have shown similar results [80].

Clinically probable MSA — The diagnosis of clinically probable MSA requires all of the following (table 3) [12]:

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

At least two of:

Autonomic dysfunction defined as (at least one is required):

-Unexplained voiding difficulties with PVR of any volume

-Unexplained urinary urge incontinence

-Neurogenic orthostatic hypotension defined as a blood pressure reduction within 10 minutes of standing by ≥20 mmHg systolic or ≥10 mmHg diastolic

Parkinsonism (bradykinesia plus rigidity or tremor, irrespective of response to levodopa)

Cerebellar syndrome (at least one of gait ataxia, limb ataxia, cerebellar dysarthria, or oculomotor dysfunction)

At least one supportive motor or nonmotor clinical feature (same list as above) (see 'Clinically established MSA' above)

Absence of exclusionary features (see 'Exclusionary features' above)

As defined, the core clinical features of clinically probable MSA are more sensitive and usually manifest earlier compared with the core features of clinically established MSA [12,79]. Therefore, many patients who initially meet criteria for clinically probable MSA will go on to meet criteria for established MSA over time.

Possible prodromal MSA (research only) — Research criteria for possible prodromal MSA were added to the Movement Disorder Society (MDS) diagnostic criteria in 2022 but are not intended for clinical use. According to the criteria, possible prodromal MSA exists when all of the following are met [12]:

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

At least one clinical nonmotor feature:

RBD (polysomnography proven)

Neurogenic orthostatic hypotension (≥20 mmHg systolic blood pressure drop) within 10 minutes of standing or head-up tilt

Urogenital failure (erectile dysfunction in males below age 60 years combined with at least one of unexplained voiding difficulties with PVR >100 mL and unexplained urinary urge incontinence)

At least one clinical motor feature:

Subtle parkinsonian signs

Subtle cerebellar signs

Absence of all of the following:

Unexplained anosmia on olfactory testing and/or abnormal cardiac sympathetic imaging

Fluctuating cognition with pronounced variation in attention and alertness and early decline in visuoperceptual abilities

Recurrent visual hallucinations not induced by drugs within three years of disease onset

Dementia within three years of disease onset

Downgaze supranuclear palsy or slowing of vertical saccades

Brain MRI findings suggestive of an alternative diagnosis (eg, PSP, multiple sclerosis, vascular parkinsonism, symptomatic cerebellar disease)

Alternative condition known to produce autonomic failure, ataxia, or parkinsonism and plausibly connected to patient’s symptoms

Role of genetic testing — We do not perform genetic testing routinely in patients with probable MSA but consider it when atypical features suggest the possibility of spinocerebellar ataxia (SCA), such as younger onset, slower progression, decreased instead of increased reflexes, or positive family history. Such cases are rare, however.

In a retrospective report from Korea, 302 patients with a clinical diagnosis of probable or possible MSA (by older diagnostic criteria) had genetic testing for some of the more common types of SCA [81]. 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 4) 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 "Autosomal dominant spinocerebellar ataxias".)

DIFFERENTIAL DIAGNOSIS — It is important to distinguish MSA from Parkinson disease (PD) because of differences in prognosis and treatment. It is also important to differentiate it from other atypical parkinsonian disorders, mainly progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). In clinicopathologic studies, the accuracy of a clinical diagnosis of MSA ranges from 60 to 80 percent when compared with autopsy findings [82-84]. The distinction between MSA with predominant parkinsonism (MSA-P) and PSP can be particularly difficult during life [85]. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

Among various clinical features, we find the following clues most meaningful in the clinic when considering the diagnosis of MSA and its common mimics:

Levodopa response assessment – The primary feature that clinically distinguishes MSA-P from PD in most cases is the lack of a sustained and dramatic reduction in clinical symptoms and signs with levodopa therapy (see 'Levodopa response assessment' 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 [76,84].

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

Limb apraxia – Apraxia is a relatively unusual sign, and its presence suggests CBD rather than MSA. (See "Corticobasal degeneration".)

However, there is overlap among these conditions. MSA may sometimes present with the phenotype of PSP, including vertical eye movement abnormalities [84,85]. In addition, patients with a pure akinetic-rigid syndrome may be impossible to diagnose because PD can present in this manner.

Among patients with idiopathic adult-onset cerebellar ataxia, 21 to 33 percent will meet clinical criteria for MSA-C [16,86,87]. Disorders that may present with predominant cerebellar dysfunction and other features overlapping with MSA-C include [81,88]:

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

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

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

Pure autonomic failure (PAF) should be considered if autonomic symptoms are the predominant feature of the disorder and motor involvement is limited or absent. PAF is associated with slower functional deterioration and a better prognosis than MSA [89]. (See "Mechanisms, causes, and evaluation of orthostatic hypotension", section on 'Etiologies'.)

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

Clinical features – Multiple system atrophy (MSA) is a rare, adult-onset neurodegenerative disorder characterized by varying combinations of parkinsonism, autonomic dysfunction, cerebellar ataxia, and pyramidal signs. (See 'Clinical features' above.)

Motor involvement – Motor manifestations of MSA are classified into subtypes according to whether the predominant feature is parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C) at the time of diagnosis. Patients can have features of both, and the predominance can change over time. (See 'Motor involvement' above.)

Patients with MSA-P have 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 'Parkinsonism (MSA-P)' above and 'Cerebellar dysfunction (MSA-C)' above.)

Patients with either subtype commonly have dysphagia and altered speech, which may be hypophonic, high-pitched, or dysarthric and scanning. Postural abnormalities, such as antecollis and camptocormia, can be prominent. (See 'Speech and swallowing' above and 'Postural abnormalities' above.)

Dysautonomia – Symptomatic dysautonomia is present in nearly all patients. Common manifestations include early erectile dysfunction in males, urinary dysfunction (eg, urgency, frequency, nocturia, urge incontinence, impaired bladder emptying), constipation, and neurogenic orthostatic hypotension. (See 'Dysautonomia' above.)

Nonmotor features – A majority of patients have one or more sleep disorders, including nocturnal stridor, sleep apnea, and rapid eye movement (REM) sleep behavior disorder (RBD). Cognition and memory are relatively preserved. (See 'Nonmotor features' above.)

Neuroimaging – Brain MRI in patients with clinically established MSA may show atrophy of the putamen, pons, middle cerebellar peduncles, and cerebellum; increased diffusivity in the putamen; and a "hot cross bun" sign within the pons (image 1 and image 2). These features are supportive but not sensitive or specific for the diagnosis. (See 'Neuroimaging' above.)

Evaluation – MSA should be suspected in patients with adult-onset, progressive parkinsonism and/or cerebellar dysfunction associated with early or severe dysautonomia. History and neurologic examination are central to the diagnosis of MSA, both to confirm key clinical features of the disease and to rule out alternative and competing causes. (See 'History and neurologic examination' above.)

Levodopa responsiveness should be tested in all patients with parkinsonism. Lack of sustained response to levodopa can help to distinguish MSA from Parkinson disease (PD), but transient benefit from levodopa is observed in 30 to 50 percent of patients with MSA. (See 'Levodopa response assessment' above.)

Diagnosis – MSA is a clinical diagnosis. Diagnostic criteria for MSA recognize clinically established and clinically probable levels of certainty based on clinical features, brain MRI findings, and absence of exclusionary features (table 3). (See 'Diagnostic criteria' above.)

Differential diagnosis – MSA shares overlapping clinical features with PD, other atypical parkinsonian disorders, and adult-onset spinocerebellar ataxias (SCAs). (See 'Differential diagnosis' above.)

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