Elsevier

Autonomic Neuroscience

Volume 211, May 2018, Pages 15-25
Autonomic Neuroscience

Review
Diagnosis of multiple system atrophy

https://doi.org/10.1016/j.autneu.2017.10.007Get rights and content

Abstract

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs.

Introduction

Multiple system atrophy (MSA) is the most rapidly progressive of the synucleinopathies, a group of disorders characterized by the abnormal deposition of the protein α-synuclein (αSyn) in the central and peripheral autonomic nervous system (Roncevic et al., 2014, Wenning et al., 2013). While in patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB) αSyn predominantly accumulates in neurons forming Lewy bodies and Lewy neurites, in patients with MSA it accumulates mostly in oligodendroglial cells forming glial cytoplasmic inclusions (GCI). A significant percentage of patients with MSA present with genitourinary dysfunction and orthostatic hypotension (OH) due to dysfunction of the autonomic nervous system, frequently combined with a history suggesting rapid eye movement (REM) sleep behavior disorder (RBD). Within a few years patients go on to develop balance, speech and coordination abnormalities that progress fairly rapidly. Depending on their initial predominant motor deficits, MSA is sub-classified into a parkinsonian (MSA-P) and a cerebellar phenotype (MSA-C) (Quinn, 2015). Age at onset, prevalence of cardiovascular autonomic dysfunction, sleep disorders, and retinal abnormalities are similar in both phenotypes (Mendoza-Santiesteban et al., 2015, Palma et al., 2015, Roncevic et al., 2014). Specific neuroimaging markers differ between the cerebellar and parkinsonian phenotypes (Deguchi et al., 2015, Huppertz et al., 2016, Lee et al., 2015), as well as the degree of sudomotor dysfunction which may be more severe in patients with MSA-P (Coon et al., 2017) and urogenital dysfunction which may occur earlier in patients with MSA-C (Zheng et al., 2017).

Patients with MSA have a mean age at onset of 55–60 years, and an average survival from the onset of motor symptoms of 8–9 years, although some pathology-proven cases survived > 15 years (Fanciulli and Wenning, 2015, Petrovic et al., 2012).

MSA may be difficult to distinguish clinically from other disorders, particularly in patients at the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure (PAF) (Kaufmann et al., 2017b, Muppidi and Miglis, 2017). Patients presenting with parkinsonism may be misdiagnosed as PD. The reverse also occurs; approximately 20% of patients with a clinical diagnosis of MSA turn out to have PD or DLB at autopsy (Koga et al., 2015). Patients presenting with the cerebellar phenotype can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias (e.g., spinocerebellar ataxias, fragile X–associated tremor ataxia syndrome, or late-onset Friedreich ataxia) (Klockgether, 2010, Lin et al., 2016). Misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials.

The accurate clinical diagnosis of MSA is based on a careful medical history and meticulous neurological examination. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the diagnosis of MSA.

Section snippets

Clinical evaluation

A detailed clinical evaluation, including a medical history (Goldstein and Cheshire, 2017b), physical, and neurological examinations with special attention to gait, coordination and muscle tone, is the most important step in the evaluation of a patient with suspected MSA. The medical history should include questions about the onset and progression of motor symptoms as well as non-motor features including symptoms of cardiovascular, gastrointestinal, genitourinary, and sudomotor dysfunction;

Brain and cardiac neuroimaging

Current consensus guidelines include neuroimaging criteria for the diagnosis of possible MSA (Gilman et al., 2008) (Table 1). These include the presence of atrophy of the putamen, middle cerebellar peduncle, pons or cerebellum on brain magnetic resonance imaging (MRI), and putamen, brainstem or cerebellum hypometabolism on brain fluorodeoxyglucose (FDG) positron emission tomography (PET), as well as dopaminergic denervation on PET or single photon emission computed tomography (SPECT).

Autonomic testing

Autonomic dysfunction is a characteristic feature of MSA. Retrospective cohorts reveal that autonomic symptoms were the first manifestation of MSA in 43% of cases with MSA-P and 54% with MSA-C (Roncevic et al., 2014). The most common autonomic complaints of patients with MSA are those related to OH, neurogenic bladder (incontinence or incomplete bladder emptying), and constipation (Kaufmann et al., 2017b, Low et al., 2015, Roncevic et al., 2014).

Olfactory testing

Olfactory function has been widely studied in parkinsonian conditions, showing significant hyposmia in the majority of patients with PD (Doty, 2012), with normosmia or mild hyposmia in the majority of patients with MSA (Glass et al., 2012). Olfactory functions tests have very high specificity and moderate sensitivity to distinguish PD from MSA (Krismer et al., 2017) and, therefore, should be included in the routine evaluation of patients with suspected MSA. Interestingly, olfaction is a good

Sleep disorders

Sleep disorders in MSA are common. Virtually all patients with MSA have REM sleep behavior disorder, in many of whom is the presenting feature of the disease (Palma et al., 2015). Although sleep questionnaires appear to have a high false negative and true positive ratio, a video polysomnography is recommended to confirm RBD and rule out other sleep problems. Obstructive sleep apnea is more frequent than central sleep apnea, occurring in up to 40% of patients with MSA (Ferini-Strambi and

Urological evaluation

All patients with MSA have urinary dysfunction and this is one of the earliest feature of the disease (Kaufmann et al., 2017b, Kirchhof et al., 2003, Roncevic et al., 2014). The most frequently reported urinary symptom is voiding difficulty, present in 80% of patients followed by nocturia in 74%, urgency in 63%, incontinence in 63%, diurnal frequency in 45%, nocturnal enuresis in 19%, and urinary retention in 8% of patients (Ogawa et al., 2017). Male patients with pre-motor MSA frequently

Dysphagia evaluation

Dysphagia is severe in 32% of patients with MSA (O'Sullivan et al., 2008) and dysphagia was a subjective complaint in 73% of patients with MSA in a small study with post-mortem diagnostic confirmation (Muller et al., 2001). Because dysphagia is associated with a bad prognosis and a short survival time, it should be addressed and treated promptly. A standard dysphagia evaluation should include a modified barium swallow test or videofluoroscopy. If aspiration is mild, dietary (e.g., liquid

Cognitive evaluation

The current consensus diagnostic criteria for MSA consider dementia as a non-supporting feature of the disease (Gilman et al., 2008). There is increasing evidence, however, showing that cognitive impairment is an integral part of the disease (Koga et al., 2017, Stankovic et al., 2014). Cognitive disturbances in MSA occur across a wide spectrum ranging from mild single domain deficits to impairments in multiple domains and even to frank dementia in rare cases. Frontal-executive dysfunction is

Transcranial sonography

Although transcranial sonography is not possible in 10–20% of subjects due to reduced temporal bone acoustic window, some works suggest that substantia nigra hyperechogenicity may be a potential marker to distinguish PD from atypical parkinsonian syndromes (Bouwmans et al., 2010), either alone or in combination with other diagnostic modalities (Fujita et al., 2016).

Plasma and CSF biomarkers

There is increasing interest in the development of potential biomarkers in plasma and cerebrospinal fluid (CSF) for the diagnosis

Premotor diagnosis of multiple system atrophy

Current consensus guidelines include a possible, probable and definite diagnosis of MSA but do not include a prodromal or pre-motor category. The ability to make such a diagnosis may be near. In recent years, several prospective studies of at-risk cohorts reported the features of prodromal MSA cases. From these studies, prospective biomarkers have emerged. The accuracy of predictive diagnostic biomarkers will determine the potential eligibility for disease-modifying trials. Follow-up of

Conclusions

Although ancillary tests (olfactory testing, autonomic testing, neuroimaging, urological evaluation) can assist in the diagnosis and should be performed when possible, the diagnosis of probable or possible MSA is grounded on the clinical history and the neurological exam and can only be confirmed pathologically after the patient's death. Recent reports revealed that only 62% of patients clinically diagnosed with MSA by community neurologists have the correct diagnosis at autopsy (Koga et al.,

Funding sources

National Institutes of Health (U54 NS065736) and Dysautonomia Foundation, Inc.

Conflict of interests

All authors report no conflict of interests related to this article.

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