Multiple System Atrophy Workup

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

Approach Considerations

Multiple system atrophy (MSA) is a difficult diagnosis, especially early in the clinical course, and the initial physician often misdiagnoses the condition. The most common initial diagnosis is idiopathic Parkinson disease.

The diagnosis of MSA is based mainly on clinical features (see tables 2a, 2b, 3, and 4). The presence of MSA can be definitively established only on postmortem examination. MSA is confirmed by the presence of a high density of glial cytoplasmic inclusions (GCIs) in association with degenerative changes in the striatonigral and olivopontocerebellar pathway.

In a patient with autonomic failure and orthostatic hypotension, the combination of a normal supine norepinephrine level that does not rise significantly with upright position suggests MSA.

Autonomic function testing

This can used to evaluate the distribution and severity of parasympathetic and sympathetic dysfunction. Findings include the following:

  • 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 test

Sphincter electromyography (EMG)

Sphincter electromyography (EMG) can be used to detect hyperreflexia of the detrusor.

Measurement of urine residual volume by ultrasonography

Incomplete bladder emptying of greater than 100ml can be detected through ultrasonography.

Detrusor contractions

Impaired detrusor contractility is the pathognomonic urodynamic finding that distinguishes MSA from PD. [30]

Scintigraphy

Scintigraphy with iodine-123 metaiodobenzylguanidine (123 I MIBG) appears to be a useful tool for differentiation between Parkinson disease and MSA early after onset of autonomic dysfunction (90% sensitivity, 95% specificity).

Patients with Parkinson disease have significantly lower cardiac123 I MIBG uptake than do some patients with MSA and controls. However, studies have shown imperfect reliability. [31, 32]

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MRI

Brain images may be normal in MSA. However, olivopontocerebellar atrophy (OPCA), cerebellar atrophy, and the putaminal lesions of striatonigral degeneration are often detected using MRI 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. [33]

Expected MRI findings in MSA are as follows:

  • Atrophy of cerebellum and brainstem in OPCA and striatonigral degeneration (SND)

  • No vascular damage

  • No multi-infarct pattern in brain

  • No other lesions

  • Hyperintensity in the pons, peduncles, and cerebellum on T2-weighted and proton density–weighted MRI scans

  • Slitlike hyperintensity on T2-weighted and proton density–weighted MRI scans; a cruciform hyperintensity in the pons on T2-weighted MRI, known as the hot cross bun sign, is diagnostically helpful, but it is not specific to MSA. [34]

In addition, MRI and proton MR studies can be used to exclude other conditions, such as multi-infarct syndromes.

Trace (D)

A study using diffusion-weighted MRI showed that patients with MSA with predominant parkinsonism (MSA-P) had significantly higher Trace (D) values in the entire and anterior putamen, whereas patients with MSA with cerebellar features (MSA-C) 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 patients with MSA-P and in the cerebellum and middle cerebellar peduncle of patients with MSA-C. [35]

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PET Scanning

MSA can be differentiated from Parkinson disease with the use of FDG-PET scanning. The caudate-putamen index, which is calculated 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. [36]

Expected findings in MSA are as follows:

  • Reduced putaminal FDG uptake

  • Reduced [11 C]raclopride and [11 C]diprenorphine levels

  • Reduced cerebellar glucose metabolism in OPCA

Absence of parkinsonian features but evidence of striatonigral dopaminergic denervation may point to MSA.

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Histologic Findings

Neuropathologic changes in MSA consist of the development 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 brainstem

  • Intermediolateral cell columns

  • Anterior horn cells

  • Onuf nuclei in the spinal cord and pyramidal tracts

GCIs, which can be stained using the Gallyas silver technique, range from sickle shaped 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 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. (See Table 8, below.)

Table 8. Differences Between GCIs in MSA and Other Pathologic Inclusions and Structures (Open Table in a new window)

 

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

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