Multiple System Atrophy Differential Diagnoses

Updated: Oct 17, 2018
  • Author: André Diedrich, MD, PhD; Chief Editor: Selim R Benbadis, MD  more...
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Diagnostic Considerations

MSA and Parkinson disease

Parkinsonian symptoms can occur frequently in multiple system atrophy (MSA). Approximately 10% of patients with a diagnosis of Parkinson disease are found to have MSA at autopsy. About 29-33% of patients with isolated, late-onset cerebellar ataxia will eventually develop MSA.

Clinical differentiation of Parkinson disease from MSA is extremely difficult. MSA is suggested by the following characteristics:

  • Disability progresses rapidly

  • Patients are poorly responsive to levodopa

  • Autonomic features such as urinary retention or incontinence or orthostatic hypotension are pronounced

  • Rigidity and bradykinesia are out of proportion to tremor

  • Speech is affected severely (dysarthrophonia, severe dysarthria)

  • Aspiration, inspiratory gasps, and stridor are present

Preliminary results of an ongoing comparison study indicate that autonomic indices are significantly more abnormal in MSA than in Parkinson disease. [24]

Wenning et al developed a predictive model based on established pathologic data from patients with MSA and Parkinson disease. [25] The model contains the following features:

  • Poor response to levodopa

  • Autonomic features

  • Speech or bulbar dysfunction

  • Absence of dementia

  • Absence of levodopa-induced confusion

  • Falls

Table 6 (below) further outlines some distinctive features of MSA and Parkinson disease.

Table 6. Differential Diagnosis of MSA and Parkinson Disease [26] (Open Table in a new window)

Characteristic

MSA

Parkinson Disease

Response to chronic levodopa therapy*

Poor or unsustained motor response because of loss of postsynaptic dopamine receptors

Initial improvement in 30% of patients with MSA, but 90% were unresponsive over a longer time; 50% develop levodopa-induced dyskinesia of orofacial and neck muscles

Good response

Effects on striatonigral transmission

Presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum, as well as their striatal target cells, have reduced dopamine receptors

Presynaptic

Symmetry of movement disorder

Possibly asymmetrical

No data

Progression of symptoms

Rapid

Slow

Postural instability and falling**

Early

Fast progression

Worsen >20% of UPDRS scale**

Late

Less progression (< 10%)

Progress of disability

Relatively fast disability; 30% decrease of activities of daily living in 1 year; 40% of patients in a wheelchair within 5 years (wheel chair sign)

Relatively slow disability

Abnormal speech

Severely affected speech in 30% of patients with MSA

Dysarthrophonia and severe dysarthria are common

Less affected

Abnormal Respiration

Abnormal aspiration, inspiratory gasps, and stridor in 60% of patients with MSA

Stridor caused by paralysis of vocal cord occurs especially at night but is also present during day

Less common

Lewy bodies (hyaline eosinophilic cytoplasmic neuronal inclusions)

Not present***

Primarily in substantia nigra

Cytoplasmic inclusions (immunocytochemical reaction with antibodies to alpha synuclein)

Glial inclusions; argyrophilic cellular inclusions in oligodendrocytes

Absent

Thermoregulation, skin perfusion

Cold hands and decrease of warm-up after cold-pack stimulus

Normal

Caudate-putamen index of dopamine uptake (on positron emission tomography [PET] scanning)

Decreased in putamen and caudate

Decreased in putamen with smaller decrease in caudate

Growth hormone release with intravenous (IV) injection of clonidine

No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)

Increase of growth hormone, intact function

* A positive response to levodopa is defined as a significant improvement of motor features during 3 months’ application of escalating doses of levodopa with a peripheral decarboxylase inhibitor. [6]

** Postural instability as defined by item 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor examination). [6]

*** Pakiam et al reported that patients with diffuse Lewy-body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling some proposed criteria for the striatonigral form of MSA. [27]

MSA and PAF

Patients with MSA who present with only autonomic and urinary dysfunction can be incorrectly identified as having pure autonomic failure (PAF).

Bradbury and Eggleston first described PAF as idiopathic hypotension, [28] but current criteria imply failure of the autonomic nervous system in the absence of extrapyramidal, pyramidal, or cerebellar abnormalities. MSA is distinct from PAF.

The sympathetic and parasympathetic systems are centrally impaired in MSA, whereas the involvement is peripheral in PAF. The progression of MSA is faster than that of PAF, and the prognosis is poor.

Lewy bodies are common in PAF at many sites, even occasionally in the heart, but they are not present in MSA. (Exception: In 1999, Pakiam et al reported 1 case in which a patient with diffuse Lewy-body disease presented with parkinsonism and prominent autonomic dysfunction, fulfilling proposed criteria for the striatonigral form of MSA. [27] ) Instead of Lewy bodies, patients with MSA have oligodendroglial cytoplasmic inclusions. Low plasma norepinephrine levels also usually indicate PAF.

Table 7, below, summarizes the distinctive features of MSA and PAF. Early (eg, years 1-2) in the disease process, the distinction may be difficult, but distinguishing findings are usually evident during follow-up care.

Table 7. Differential Diagnosis of MSA and PAF (Open Table in a new window)

Characteristic

MSA

Pure Autonomic Failure

CNS involvement

Multiple involvement

Unaffected

Site of lesion

Mainly preganglionic, central; degeneration of intermediolateral cell columns; ganglionic neurons relatively intact

Mainly postganglionic; loss of ganglionic neurons

Progression

Fast; median survival 6.5-9.5 years

Slow; some patients survive >10-30 years

Prognosis

Poor

Good

Extrapyramidal involvement

Common

Not present

Cerebellar involvement

Common

Not present

Gastrointestinal symptoms

Uncommon

Absent, except constipation

Plasma supine norepinephrine level

Normal

Reduced

Antidiuretic hormone (ADH) response to tilt

Impaired because of catecholaminergic denervation of hypothalamus (but normal ADH response to osmotic stimuli)

Maintained

Adrenocorticotropic hormone and beta-endorphin response to hypoglycemia

Impaired because of central cholinergic dysfunction or dysfunction of adrenergic input to paraventricular nucleus

Normal

Growth hormone release with clonidine IV injection

No release, dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)

Increase of growth hormone; intact function

Substance P, catecholamine, 5-HT, and acetylcholine markers in cerebrospinal fluid

Decreased levels

No data

Lewy bodies

Mostly absent

Present in autonomic neurons

BP response to oral water intake

Increased

Increased but variable

BP response to ganglionic blockade

Profound decrease

Modest decrease

MSA and PSP

Progressive supranuclear palsy (PSP), also known as the Steele-Richardson-Olszewski syndrome, is characterized by neuronal degeneration and neurofibrillary tangles affecting the pons and midbrain. The clinical picture of PSP may be similar to that of MSA. Cardiovascular autonomic dysfunction is an exclusionary feature in the diagnosis of PSP. [29]

Analysis of the horizontal and vertical eye movements may help to distinguish PSP from MSA. Patients with PSP demonstrate slowing of saccades, which is not the situation in MSA. The trajectories of saccades made to diagonal target jumps are deviated toward the horizontal plane; because of the vertical hypometria, this is more pronounced in patients with PSP than in those with MSA. The patient with PSP may be prone to falls because of impaired downward gaze.

Persons with PSP and those with MSA demonstrate different responses to pharmacologic and physiologic stimuli in autonomic function tests. [29]

MSA and corticobasal ganglionic degeneration

Corticobasal ganglionic degeneration is pathologically characterized by enlarged, achromatic neurons in cortical areas and nigral and striatal neuronal degeneration. The onset is typically unilateral, with marked rigidity-dystonia of the involved arm; this differs from MSA.

Cortical signs of apraxia, alien-limb phenomena, cortical sensory loss, and cortical reflex myoclonus are helpful to distinguish between corticobasal ganglionic degeneration and MSA.

MSA and cerebrovascular syndromes

Cerebrovascular syndromes (eg, multi-infarct lesions in the brain) may demonstrate features similar to those of MSA. Dementia is not common in MSA. Brain MRI helps to exclude cerebrovascular diseases.

Other conditions

Other disorders to consider in the differential diagnosis of MSA include the following:

  • Fragile X-associated tremor/ataxia syndrome (FXTAS)

  • Mitochondrial cytopathies

  • Paraneoplastic Disease

  • Neurosarcoidosis

Differential Diagnoses