eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Multiple System Atrophy: Differential Diagnoses & Workup

Author: André Diedrich, MD, PhD, Research Associate Professor of Medicine, Research Assistant Professor of Biomedical Engineering, Autonomic Dysfunction Center, Vanderbilt University School of Medicine
Coauthor(s): David Robertson, MD, Director, Clinical Research Center, Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University
Contributor Information and Disclosures

Updated: Sep 4, 2009

Differential Diagnoses

Other Problems to Be Considered

Differentials to other diseases

• MSA and Parkinson disease
  • Parkinsonian symptoms can occur frequently in 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 and MSA is extremely difficult. MSA is suggested when (1) disability progresses rapidly,(2) patients are poorly responsive to levodopa,(3) autonomic features such as urinary retention or incontinence or orthostatic hypotension are pronounced,(4) rigidity and bradykinesia are out of proportion to tremor,(5) speech is affected severely (dysarthrophonia, severe dysarthria), and(6) abnormal aspiration, inspiratory gaps, and stridor are present.
  • Table 6 outlines some distinctive features. 
  • Wenning et al developed a predictive model based on established pathologic data from patients with MSA and Parkinson disease.⁸³ The new model contains the following features: poor response to levodopa, autonomic features, speech or bulbar dysfunction, absence of dementia, absence of levodopa-induced confusion, and falls. Preliminary results of an ongoing  comparison study indicate that autonomic indices are highly significantly more abnormal in MSA than in Parkinson disease.⁹¹

Table 6. Differential Diagnosis of MSA and Parkinson Disease

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Table

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 longer time of intake; 50% develop L-dopa induced dyskinesia of orofacial and neck muscles	Good response
Effects on nigrostriatal transmission	Both presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum and their striatal target cells have reduced dopamine receptors	Presynaptic
Symmetry of movement disorder	Possibly asymmetric	No data
Progression of symptoms	Rapid	Slow
Instability and falling	Early	Late
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 gaps, 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 anti-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])	Decreased in putamen and caudate	Decreased in putamen with smaller decrease in caudate
Growth hormone release with intravenous injection of clonidine	No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)	Increase of growth hormone, intact function

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 longer time of intake; 50% develop L-dopa induced dyskinesia of orofacial and neck muscles	Good response
Effects on nigrostriatal transmission	Both presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum and their striatal target cells have reduced dopamine receptors	Presynaptic
Symmetry of movement disorder	Possibly asymmetric	No data
Progression of symptoms	Rapid	Slow
Instability and falling	Early	Late
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 gaps, 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 anti-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])	Decreased in putamen and caudate	Decreased in putamen with smaller decrease in caudate
Growth hormone release with intravenous injection of clonidine	No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)	Increase of growth hormone, intact function

*

Pakiam et al reported that patients with diffuse Lewy-body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling proposed criteria for the striatonigral form of MSA.⁵⁸

• MSA and PAF
  • Patients with MSA who present with only autonomic and urinary dysfunction can be incorrectly identified as having PAF.
  • Bradbury and Eggleston first described PAF as idiopathic hypotension in 1925,⁸ 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.⁵⁸ )
  • Instead of Lewy bodies, patients with MSA have oligodendroglial cytoplasmic inclusions.
  • Low plasma norepinephrine levels usually indicate PAF.
  • Vasopressor response to tilt also can assist in making the diagnosis.
  • Table 7 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 in MSA and PAF

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    Table

    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 >10-15 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 intravenous 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

    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 >10-15 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 intravenous 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 progressive supranuclear palsy (PSP), or Steele-Richardson-Olszewski syndrome
  • Progressive supranuclear palsy (PSP), also known as the Steele-Richardson-Olszewski syndrome, is characterized by neuronal degeneration and neurofibrillary tangles affecting the pons and mid brain.
  • The clinical picture of PSP may be similar to that of MSA.
  • Analysis of the horizontal and vertical eye movements may help to distinguish PSP and 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.
  • PSP subjects and MSA subjects demonstrated different responses to pharmacologic and physiologic stimuli in autonomic function tests.⁴¹
  • Cardiovascular autonomic dysfunction should be an exclusionary feature in the diagnosis of PSP.⁴¹
• 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, which 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.
• Differential of 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.

Workup

Laboratory Studies

• The diagnosis of MSA is based mainly on clinical features (see Table 2, Table 3, Table 4).
• Definite MSA can be established only on postmortem examination. MSA is confirmed by the presence of a high density of GCIs in association with degenerative changes in the nigrostriatal and olivopontocerebellar pathway.
• The combination of a normal supine norepinephrine level and a low upright norepinephrine level can assist in the diagnostic process.

Imaging Studies

• Iodine-123 (¹²³ I) metaiodobenzylguanidine (MIBG) scintigraphy
  • Scintigraphy with¹²³ I MIBG appears to be a useful tool for differentiation between Parkinson disease and MSA early after onset of autonomic dysfunction (90% sensitivity and 95% specificity).
  • Patients with Parkinson disease have cardiac¹²³ I MIBG uptake significantly lower than that of patients with MSA and controls.
• Neuroimaging to exclude other conditions - MRI and proton magnetic resonance (MR) study
  • Brain images may be normal in MSA. OPCA, and cerebellar atrophy, and the putaminal lesions of striatonigral degeneration are often detected by using MR techniques.
  • The slight hyperintensity of the lateral margin of the putamen on T2-weighted MRI is a characteristic finding in patients with MSA involving the extrapyramidal system.
  • MRI findings can help to exclude cerebrovascular diseases, such as multi-infarct syndromes.
  • Expected findings are as follows:
    • Atrophy of cerebellum and brainstem in OPCA and SND
    • No vascular damage
    • No multi-infarct pattern in brain
    • No other lesions
    • Hyperintensity in pons, peduncles, and cerebellum on T2-weighted and proton density–weighted MRIs
    • Slitlike hyperintensity on T2-weighted and proton density–weighted MRIs; a cruciform hyperintensity in the pons on T2-weighted MRI, known as the hot cross bun sign, is not specific to MSA.⁹⁴

• In a study comparing the results of diffusion-weighted MRI in MSA-P patients, MSA-C patients, and normal controls, Pellecchia et al found that MSA-P patients had significantly higher Trace (D) values in the entire and anterior putamen, whereas MSA-C patients had significantly higher Trace (D) values in the cerebellum and middle cerebellar peduncle. Furthermore, increased disease duration correlated significantly with increased Trace (D) values in the pons of MSA-P patients and in cerebellum and middle cerebellar peduncle of MSA-C patients.⁹³

Positron emission tomography

• 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) PET can be used to differentiate MSA and Parkinson disease.
• The caudate-putamen index, which is calculated by using a formula based on the difference in the uptakes in the caudate and putamen divided by the caudate uptake, is lower in patients with MSA than in patients with Parkinson disease.
• Expected findings are as follows:
  • Reduced putaminal FDG uptake
  • Reduced [¹¹ C]raclopride and [¹¹ C]diprenorphine levels
  • Reduced cerebellar glucose metabolism in OPCA

Other Tests

• Autonomic function testing - Evaluation of the distribution and severity of parasympathetic and sympathetic dysfunction
  • Diminished respiratory sinus arrhythmia
  • Abnormal response to Valsalva maneuver (no BP recovery in late phase II and/or no overshoot in phase IV, reduced Valsalva ratio for heart rate)
  • Reduced response to isometric exercise (handgrip)
  • Diminished response to cold pressor stimuli
• Sphincter electromyography (EMG) - Hyperreflexia of detrusor

Histologic Findings

Neuropathologic changes consist of a high density of GCIs in association with degenerative changes in some or all of the following structures. Table 5 provides an overview of the clinicopathologic correlation.

• Putamen
• Caudate nucleus
• Globus pallidus
• Thalamus
• Subthalamic nucleus
• Substantia nigra
• Locus ceruleus
• Dorsal vagal nucleus
• Vestibular nuclei
• Pontine nuclei
• Inferior olives
• Pontine nuclei
• Cerebellar Purkinje cells
• Autonomic nuclei of the brain stem
• Intermediolateral cell columns
• Anterior horn cells
• Onuf nuclei in the spinal cord and pyramidal tracts

GCIs can be stained by using the Gallyas silver technique and are a hallmark of MSA. They range from sickle-to-flame shaped to ovoid, on occasion, superficially resembling neurofibrillary tangles. GCIs are loosely aggregated filaments with cross-sectional diameters of 20-30 nm. These filaments often entrap cytoplasmic organelles (eg, mitochondria, secretory vesicles), have no limiting membrane, and are reported to have tubular profiles and electrodense granules along much of their lengths. GCIs are ubiquitin-positive, tau-positive, and alpha-synuclein-positive oligodendroglial inclusions. They are different from Lewy bodies and neurofibrillary structures in Alzheimer disease (Table 8).

Table 8. Differences Between GCIs in MSA and Other Pathologic Inclusions and Structures

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Table

	GCIs in MSA	Lewy Bodies in Parkinson Disease	Neurofibrillary Pathology in Alzheimer Disease	Glial Lesions in Corticobasal and Progressive Supranuclear Palsy
Shape	Sickle-to-flame shaped to ovoid, various neurofibrillary tangles	Target-shaped inclusions	Tangles	Tufted astrocytes, coiled bodies
Membrane	No limiting membrane; tubular profiles and electrodense granules	Present	Present	Present
Ultrastructure	Loosely aggregated filaments	No data	No data	Astrocytic plaques
Immunocytochemistry	Ubiquitin positive, alpha-B-crystallin (synuclein) positive, alpha- and beta-tubulin positive, tau-protein positive	Hyaline eosinophilic cytoplasmic neuronal inclusions, ubiquitin	No data	Absence from phosphorylated tau
Localization	In oligodendroglial cells and neurons	In neuronal cells and oligodendroglial cells	No data	No data

	GCIs in MSA	Lewy Bodies in Parkinson Disease	Neurofibrillary Pathology in Alzheimer Disease	Glial Lesions in Corticobasal and Progressive Supranuclear Palsy
Shape	Sickle-to-flame shaped to ovoid, various neurofibrillary tangles	Target-shaped inclusions	Tangles	Tufted astrocytes, coiled bodies
Membrane	No limiting membrane; tubular profiles and electrodense granules	Present	Present	Present
Ultrastructure	Loosely aggregated filaments	No data	No data	Astrocytic plaques
Immunocytochemistry	Ubiquitin positive, alpha-B-crystallin (synuclein) positive, alpha- and beta-tubulin positive, tau-protein positive	Hyaline eosinophilic cytoplasmic neuronal inclusions, ubiquitin	No data	Absence from phosphorylated tau
Localization	In oligodendroglial cells and neurons	In neuronal cells and oligodendroglial cells	No data	No data

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