Multiple system atrophy

Differential diagnosis
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By Robert Fekete MD

Clinical and imaging findings of sporadic adult-onset ataxia of unknown etiology have some overlap with multiple system atrophy (Abele et al 2007). Although multiple system atrophy is considered a sporadic disease, 4 families, 1 of which had a consanguineous marriage, were reported with familial cases of multiple system atrophy phenotype with autonomic failure, parkinsonism, and cerebellar ataxia (Hara et al 2007). These patients were negative for spinocerebellar ataxia types 1, 2, 3, 6, 7, 12, 17, dentatorubral-pallidoluysian atrophy, and alpha-synuclein mutations.

Spinocerebellar ataxia type 2 may present with a parkinsonian or cerebellar phenotype and should be considered in the differential diagnosis, especially if an autosomal dominant inheritance pattern is established (Lastres-Becker et al 2008; Yomono et al 2010). Spinocerebellar ataxia type 3 has also been reported with a multiple system atrophy phenotype (Wullner et al 2007). Aprataxin mutations leading to ataxia with oculomotor apraxia can also have an overlapping phenotype with MSA-C (Baba et al 2007).

Autonomic dysfunction in late-onset cerebellar ataxia complicates differential diagnosis with MSA-C (Lin et al 2014). An SCA17 case with progressive ataxia, autonomic dysfunction, parkinsonism, supranuclear gaze palsy, and cognitive impairment has been reported (Lin et al 2007). A case of SCA17 with reduced penetrance given 41 CAG repeats (44 repeats are needed for full penetrance) was reported. This patient had lack of putaminal hyperintense rim, but did have urinary incontinence and erectile dysfunction. Although he fulfilled diagnostic criteria for probable multiple system atrophy, the overall clinical picture was more consistent with SCA17 (Doherty et al 2014). In contrast, a series of 199 patients with a clinical diagnosis of multiple system atrophy was negative for SCA12 (Cho et al 2008b). In addition, hereditary spastic paraplegias, fragile-X tremor ataxia syndrome (FXTAS), mitochondrial disease, Gaucher disease, Perry syndrome, and cerebrotendinous xanthomatosis can potentially mimic multiple system atrophy (Stamelou et al 2013).

“Red flags” with greater than 95% specificity for MSA-P as opposed to Parkinson disease include postural instability within 3 years of disease onset and resulting recurrent falls, wheelchair dependency within 10 years of onset, Pisa syndrome (prolonged episodes of lateral trunk flexion), disproportionate antecollis (van de Warrenburg et al 2007), contractures of hands or feet excluding Dupuytren disease, diurnal inspiratory stridor, nocturnal inspiratory stridor, inspiratory sighs, severe dysphonia, severe dysarthria, severe dysphagia, and emotional incontinence (Kollensperger et al 2008). Laryngeal abductor paralysis (Nagata et al 2007), generally occurring in advanced stages of multiple system atrophy, has also been reported in the early stages (Deguchi et al 2007b). It may lead to nocturnal sudden death (Egami et al 2007). “Cold hand sign,” with poor circulatory return after blanching, is a clue for multiple system atrophy with poorly understood pathophysiology (Pietzarka et al 2010). Lower limb tremor, although a possible presentation of Parkinson disease, may be suspicious for multiple system atrophy (Hellmann et al 2010). Symmetric symptoms, which were reported in 48% of a cohort of MSA-P patients, should also increase suspicion for this disorder when evaluating Parkinson disease patients (Gomez-Esteban et al 2010). Emotional incontinence exhibited by inappropriate laughter or crying has also been reported in 36% of a series of MSA-C patients (Parvizi et al 2007). “Cold hand sign” with palmar skin temperature less than 28°C was reported in 6% of multiple system atrophy cases and no Parkinson disease or normal control cases (Asahina et al 2013).

The presence of excessive square-wave jerks, mild to moderate hypometria of saccades, impaired vestibulo-ocular reflex suppression, spontaneous nystagmus, or positioning downbeat nystagmus may be oculomotor clues to the presence of multiple system atrophy, whereas the presence of clinically slow saccades or moderate to severe gaze restriction argues against multiple system atrophy (Anderson et al 2008). Of note, hypometric saccades have been reported in Parkinson disease (Armstrong 2008). Ocular jaw synkinesia, described in Parkinson disease, is not seen in MSA-P (Salazar et al 2010).

Differentiation of MSA-P from the subset of Parkinson disease and diffuse Lewy body disease (DLB) patients with prominent autonomic failure is a profound diagnostic challenge. In a retrospective study of 134 patients with clinical diagnosis of multiple system atrophy on whom subsequent pathological evaluation was performed, the diagnostic accuracy of multiple system atrophy versus diffuse Lewy body disease, Parkinson disease, and progressive supranuclear palsy was 64%, with autonomic failure in diffuse Lewy body disease and Parkinson disease patients as the main cause of misdiagnosis of multiple system atrophy (Koga et al 2015). In a prospective study of multiple system atrophy and Parkinson disease patients, scores on self-report questionnaires of autonomic symptoms as well as on clinical assessments of autonomic function were similar in the 2 groups (Lipp et al 2009). The pattern of anhidrosis is different in the 2 groups. Intact quantitative sudomotor axon testing in anhidrotic areas confirmed a preganglionic lesion in multiple system atrophy patients, whereas Parkinson disease patients had anhidrosis due to a peripheral lesion (Lipp et al 2009). Postganglionic sudomotor denervation reported in a study confounds this diagnostic method (Provitera et al 2014).

Alpha-synuclein pathology was seen on colonic biopsy of the enteric nervous system in 1 out of 6 multiple system atrophy patients and in 5 out of 9 Parkinson disease patients (Pouclet 2012). Thus, although synuclein pathology is less common in multiple system atrophy than in Parkinson disease, it may involve the entire enteric nervous system.

Although progressive supranuclear palsy parkinsonism (PSP-P) shares many features with multiple system atrophy, autonomic dysfunction is uncommon in this disorder and can help distinguish it from multiple system atrophy (Williams and Lees 2010). In a study by Koga and colleagues, the prominent cerebellar features of the cerebellar subtype of progressive supranuclear palsy (PSP-C) led to misdiagnosis as MSA-C (Koga et al 2015).

Corticobasal degeneration may be confused with multiple system atrophy, but the former is highly asymmetric and always shows important apraxia and cortical sensory loss. The multiple system atrophy with a predominance of dysautonomia may be confused with progressive autonomic failure. However, the dysautonomic features in multiple system atrophy typically start with bladder and erectile dysfunction, proceeding to thermoregulatory difficulty and orthostatic hypotension, and finally to ventilatory dysrhythmias. Progressive autonomic failure, on the other hand, begins with thermoregulatory and blood pressure dysregulation; bladder dysfunction occurs last, and ventilatory arrhythmias do not occur (Mabuchi 2005).

In a large series of patients carrying a diagnosis of multiple system atrophy of the cerebellar type, 4% (3 of 76 patients) had a mutation in the FMR1 gene, suggesting that fragile-X-associated tremor-ataxia syndrome should be considered in the differential diagnosis (Kamm et al 2005).

Multi-infarct states may mimic multiple system atrophy and many other degenerative disorders but are usually identified by vascular lesions on MRI scan, arteriosclerotic risk factors, and a history of stepwise progression. Additionally, a rare case of multiple system atrophy masking symptoms of multiple sclerosis has been reported (Finke et al 2010). Cases of pure autonomic failure do not have the additional parkinsonian or cerebellar signs of multiple system atrophy on physical examination.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited