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Multiple System Atrophy Differential Diagnoses

  • Author: André Diedrich, MD, PhD; Chief Editor: Selim R Benbadis, MD  more...
 
Updated: Jul 08, 2016
 
 

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

 
 
Contributor Information and Disclosures
Author

André Diedrich, MD, PhD Research Professor of Medicine, Adjunct Research Professor of Biomedical Engineering, Director of the Analytical and Phenotyping Core, Autonomic Dysfunction Center, Vanderbilt University School of Medicine

André Diedrich, MD, PhD is a member of the following medical societies: American Autonomic Society

Disclosure: Nothing to disclose.

Coauthor(s)

David Robertson, MD Director, Clinical and Translational Research Center, Vanderbilt Institute for Clinical and Translational Research, Principal Investigator, Autonomic Rare Disease Clinical Research Consortium, Elton Yates Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University School of Medicine

David Robertson, MD is a member of the following medical societies: American Heart Association, Association of American Physicians

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cyberonics; Eisai; Lundbeck; Sunovion; UCB; Upsher-Smith<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cyberonics; Eisai; Glaxo Smith Kline; Lundbeck; Sunovion; UCB<br/>Received research grant from: Cyberonics; Lundbeck; Sepracor; Sunovion; UCB; Upsher-Smith.

Acknowledgements

Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society

Disclosure: Nothing to disclose.

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Table 1. Historical Milestones in the Definition of Terms for MSA
Term Period Authors Comments
Olivopontocerebellar atrophy (OPCA) 1900 Dejerine and Thomas Introduction of the term olivopontocerebellar atrophy
Orthostatic hypotension (OH) 1925 Bradbury and Eggleston Introduction of autonomic failure as a clinical syndrome
Shy-Drager syndrome (SDS) 1960 Shy and Drager Origin of this term as a neuropathologic entity with parkinsonism and autonomic failure with OH
Striatonigral degeneration (SND) 1960 Van der Eecken et al Description of SND
Multiple system atrophy (MSA) 1969 Graham and Oppenheimer Introduction of the term MSA, which represents SDS, SND, and OPCA as 1 entity
Glial cytoplasmic inclusions (GCIs) 1989 Papp et al, Matsuo et al Discovery of GCIs as hallmark of MSA
Alpha-synuclein inclusion 1998 Spillantini et al, Wakabayashi et al Alpha-synuclein immunostaining as a sensitive marker of MSA
MSA classification 1996-1999 Consensus Committee Classification of MSA based on clinical domains and features and neuropathology
Unified MSA Rating Scale (UMSARS) 2003 European MSA Study Group Unified MSA Rating Scale as a standard to define MSA symptoms[4, 5]
Second consensus for MSA 2007 Consensus Committee New definition of MSA with simplified criteria
Table 2a. Main Features for the Diagnosis of MSA
Clinical Domain Feature Comment
Autonomic



dysfunction



Severe orthostatic hypotension (OH)
  • Asymptomatic
  • Symptomatic
OH is defined as blood pressure fall by at least 30mm Hg systolic and 15mm Hg diastolic within 3 minutes of standing from a previous 3-minute interval in the recumbent position.**
Urogenital dysfunction Urinary incontinence (UI) or incomplete bladder emptying UI is defined as persistent, involuntary, partial or total bladder emptying.



ED usually occurs before symptomatic OH.***



Erectile dysfunction (ED) in men
Parkinsonian features



(87% incidence *)



Bradykinesia (BK) BK is slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions.



PI not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction.



Rigidity
Postural instability (PI)
Tremor - Postural, resting, or both
Cerebellar dysfunction



(54% incidence *)



Gait ataxia (GA) GA is a wide-based stance with steps of irregular length and direction.



Sustained gaze-evoked nystagmus



Ataxic dysarthria
Limb ataxia
Oculomotor dysfunction
Coritcospinal tract dysfunction Extensor plantar response with hyperreflexia Babinsky sign, Pyramidal sign
*Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al[2] ).



**OH caused by drugs, food, temperature, deconditioning, or diabetes are excluded.



***ED does not count in the definition of onset of disease, because it is a general feature in older people.



Table 2b. Additional Features for the Diagnosis of Possible MSA*
Category Additional Features
 



Possible



MSA-P



Possible



MSA-C



  • Babinski sign with hyperreflexia
  • Stridor
 



Possible



MSA-P



  • Rapidly progressive parkinsonism
  • Poor response to levodopa
  • Postural instability within 3 years of motor onset
  • Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
  • Dysphagia within 5 years of motor onset
  • Atrophy on magnetic resonance imaging (MRI) of putamen, middle cerebellar peduncle, pons, or cerebellum
  • Hypometabolism on 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scanning in putamen, brainstem, or cerebellum
 



Possible



MSA-C



 
  • Parkinsonism (bradykinesia and rigidity)
  • Atrophy on MRI of the putamen, middle cerebellar peduncle, or pons
  • Hypometabolism on FDG-PET in the putamen
  • Presynaptic striatonigral dopaminergic denervation on single-photon emission computed tomography (SPECT) or PET scanning
*Modified from second consensus[6]
Table 3. Characteristics That Do Not Support the Diagnosis of MSA
Procedure Nonsupporting Features
History taking
  • Symptomatic onset at < 30 years
  • Onset after age 75 years
  • Family history of ataxia or parkinsonism
  • Systemic diseases or other identifiable causes for features listed in Table 2a
  • Hallucinations unrelated to medication
  • Dementia
Physical examination
  • Classic parkinsonian pill-rolling rest tremor
  • Clinically significant neuropathy
  • Prominent slowing of vertical saccades or vertical supranuclear gaze palsy
  • Evidence of focal cortical dysfunction, such as aphasia, alien limb syndrome, and parietal dysfunction
Laboratory study
  • Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2a
  • White matter lesions suggesting multiple sclerosis
Table 4. Diagnostic Categories of MSA
Category Definition
Possible MSA A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
  • Parkinsonism or cerebellar syndrome
  • At least 1 feature of autonomic or urogenital dysfunction
  • At least 1 of the additional features from Table 2b
Probable MSA A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
  • Autonomic failure involving urinary dysfunction
  • Poorly levodopa-responsive parkinsonism or cerebellar dysfunction
Definitive MSA A sporadic, progressive, adult (>30y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in striatonigral and olivopontocerebellar pathways
*Disease onset is defined as the initial presentation of any parkinsonian or cerebellar motor problems or autonomic features (except erectile dysfunction).
Table 5. Clinicopathologic Correlations
Clinical Symptom Pathologic Findings and Location of Damage or Cell Loss
Orthostatic hypotension Primary preganglionic damage of intermediolateral cell columns
Urinary incontinence (not retention) Preganglionic cell loss in spinal cord (intermediolateral cell columns), related to detrusor hyperreflexia caused mainly by loss of inhibitory input to pontine micturition center (rather than to external urethral sphincter denervation alone)
Urinary retention caused by detrusor atonia Sacral intermediolateral cell columns
Cerebellar ataxia Cell loss in inferior olives, pontine nuclei, and cerebellar cortex
Pyramidal signs Pyramidal tract demyelination
Extensor plantar response Pyramidal tract lesion
Hyperreflexia Pyramidal tract lesion
Motor abnormalities GCIs in cortical motor areas or basal ganglia
Akinesia Putamen, globus pallidus
Rigidity Putaminal (not nigral) damage
Limb and gait ataxia Inferior olives, basis pontis
Decreased or absent levodopa responsiveness Striatal cell loss, loss of D1 and D2 receptors in striatum or impaired functional coupling of D1 and D2 receptors
Nystagmus Inferior olives, pontine nuclei
Dysarthria Pontine nuclei
Laryngeal stridor Severe cell loss in nucleus ambiguus or biochemical defect causing atrophy of posterior cricoarytenoid muscles
Excessive daytime sleepiness Loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons[13]
Adapted from Wenning et al and other sources.
Table 6. Differential Diagnosis of MSA and Parkinson Disease [26]
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]



Table 7. Differential Diagnosis of MSA and PAF
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
Table 8. Differences Between GCIs in MSA and Other Pathologic Inclusions and Structures
  GCIs in MSA Lewy Bodies in Parkinson Disease Neurofibrillary Pathology in Alzheimer Disease Glial Lesions in Corticobasal and Progressive Supranuclear Palsy
Shape Sickle shaped 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 of phosphorylated tau
Localization In oligodendroglial cells and neurons In neuronal cells and oligodendroglial cells No data No data
Table 9. Drugs Used to Manage Orthostatic Hypotension in MSA
Class Drug Description or Mechanism
Corticosteroids Fludrocortisone (Florinef) Mineralocorticoid; sodium retention, primarily in extravascular compartment, causes tissue edema to venous capacitance bed in lower extremity. With this edema, venous bed accommodates decreased volume of blood in an upright posture (high doses, late effect); increases sensitivity to norepinephrine (even with small doses)
Sympathomimetic amines Midodrine Alpha1-adrenoreceptor agonist acts directly on vasculature, causes venous and arteriolar vasoconstriction
 



Droxidopa



 



Droxidopa is a synthetic precursor of norepinephrine. It acts by conversion to norepinephrine in the body.



Recombinant erythropoietin (EPO) Epoetin alfa Increases sensitivity to pressor effects of angiotensin II; increases plasma endothelin level; increases cytosolic free calcium in vascular smooth muscle; increases intravascular volume
NSAIDs Indomethacin, ibuprofen Inhibition of vasodilator prostaglandins proposed but not proven
Antihistamines Diphenhydramine, cimetidine Reduce vasodilatation caused by histamine release
Somatostatin analogs Octreotide Reduce splanchnic capacitance
Vasopressin agonists Desmopressin (DDAVP) Vasopressin analogs; no effect on V1 receptors, which are responsible for vasopressin-induced vasoconstriction; acts on V2 receptors on renal tubuli, which are responsible for antidiuretic effect; prevents nocturnal diuresis, raises BP in morning
Other sympathomimetics Yohimbine Alpha2-adrenoreceptor antagonist
Caffeine Adenosine receptor antagonist
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