Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized clinically by autonomic failure, parkinsonism (MSA-P) or cerebellar ataxia (MSA-C) or both, and pathologically by widespread glial cytoplasmic inclusions composed of aggregated α-synuclein [1]. The 2008 diagnostic criteria for MSA were widely accepted as diagnostic guidelines [2], but their accuracy was sub-optimal with low sensitivity, especially early in the disease [3]. Common misdiagnoses include dementia with Lewy bodies, progressive supranuclear palsy and Parkinson’s disease [3]. A Movement Disorders Society (MDS) MSA Criteria Revision Task Force was convened to develop updated diagnostic criteria and the results were published online in April 2022 in the journal Movement Disorders [4].

To develop and optimize the new criteria, the task force did a systematic literature review of clinical and laboratory features relevant to the diagnosis of MSA and carried out a consensus process with two Delphi rounds, a survey of MDS members, and a virtual consensus meeting. The new criteria define four levels of diagnostic certainty: neuropathologically established MSA, clinically established MSA and clinically probable MSA, which are similar to previous criteria, and a new category named possible prodromal MSA (Table 1). All three clinical diagnostic categories need validation in future studies and possible prodromal MSA is a research category that should be refined with emerging data.

Table 1 Diagnostic criteria for clinically established, clinically probable, and possible prodromal multiple system atrophy
Full size table

Several improvements to the previous criteria are worth discussing. Recognizing the usefulness of brain magnetic resonance imaging (MRI) in the diagnosis of MSA [5], MRI findings classically seen in these patients, e.g., pontine and/or cerebellar atrophy, “hot cross bun” sign, putaminal hyperintense rim on T2 sequences are now required for a diagnosis of clinically established MSA. The practical problems with using imaging findings in clinical diagnoses, however, is the lack of objective measurement criteria, especially in cases with equivocal MRI results. Furthermore, MRI findings of MSA may manifest later in the disease course. The role of quantitative volumetric analysis of structural MRI, advanced functional MRI modalities, or repeat brain MRI to support the diagnosis of clinically established MSA in initial “MRI-negative” cases remains subject to future research. Cardiovascular and genitourinary autonomic manifestations of MSA continue to be core clinical features of the disease (Table 1). The new criteria include simple measurements of autonomic function that can be used in clinical settings. In addition to history taking and physical examination, a 3-day bladder diary and/or measurement of postvoid residual (PVR) are sensitive to detect urogenital failure [6]. Evaluating for PVR does not necessarily require urinary catheterization and may be performed using ultrasound or a bladder scanner. A cutoff at > 100 mL PVR volume was set to secure the high specificity of a clinically established diagnosis of MSA. Objective evidence of a neurogenic etiology of orthostatic hypotension (OH) can be obtained with active standing with a ≥ 20 mmHg systolic blood pressure (SBP) drop usually accompanied by a diastolic BP (DBP) drop of ≥ 10 mmHg and a Δ heart rate (HR)/ΔSBP ratio < 0.5 beats per minute (bpm)/mmHg within 3 min of standing [7]. Due to its increased sensitivity in the diagnosis of MSA, the ≥ 20/10 mmHg BP drop replaced the ≥ 30/15 mmHg BP drop criterion of the 2008 criteria. Delayed neurogenic OH (i.e., between 3 and 10 min) was also included as a feature of clinically probable MSA. Both clinically established and clinically probable MSA require supportive motor or non-motor features (previously termed “red flags”) and the absence of exclusion criteria.

The most exciting but challenging part of the new diagnostic criteria is the introduction of possible prodromal MSA as a research category. The goal of this category is to capture MSA patients at the earliest prodromal stage, which will likely be crucial for recruitment in clinical trials of disease-modifying therapies. The essential features are either polysomnography-proven rapid eye movement sleep behavior disorder (RBD), or isolated autonomic failure, defined as at least one of urogenital failure with PVR > 100 mL or urinary urge incontinence, or neurogenic OH within 10 min of standing or HUT, as well as the presence of subtle parkinsonian motor signs or cerebellar signs (Table 1). The subtle is purposefully vague and may refer to a reduced arm swing or a slightly wide based gait for example. This category has limited specificity, especially without other imaging or laboratory biomarkers, and it should only be used for research purposes at this time. The presence of subtle signs of neurological dysfunction has been recognized in individuals with pure autonomic failure (PAF) [8]. Many patients with PAF have a slowly progressive course of autonomic dysfunction over many years, and there is a risk of categorizing some of these individuals as possible prodromal MSA. A prospective study of patients with PAF found that approximately one-third of patients met clinical criteria for another synucleinopathy, including Parkinson’s disease, dementia with Lewy bodies, or MSA, within 4 years of follow-up [9]. Patients with PAF who phenoconvert to MSA tend to do so earlier than those who later manifest a Lewy body disorder, typically within 3 years from the original PAF diagnosis [9, 10]. Applications of other laboratory and imaging biomarkers will be necessary to identify individuals in the premotor phase of MSA with high accuracy.

Most supportive biomarkers were not included in the new criteria due to their limited availability and need for validation. Nevertheless, clinicians are encouraged to investigate their presence in patients with MSA, so that more data will be available in the future. Candidate diagnostic biomarkers for MSA include brain MRI markers (for possible prodromal MSA), brain fluorodeoxyglucose–positron emission tomography markers, normal cardiac sympathetic neuroimaging, polysomnography proven RBD (for clinically established and clinically probable MSA), supine plasma norepinephrine level > 100 pg/ml in individuals with neurogenic OH, detrusor hyperactivity with impaired contraction or detrusor sphincter dyssynergia on urodynamic testing, and unexplained abnormal sphincter EMG. Other promising biomarkers include α-synuclein oligomers detected by protein aggregation assays in cerebrospinal fluid associated with increased plasma or cerebrospinal fluid neurofilament light chain.

The new MDS criteria for the diagnosis of MSA have a three-fold purpose: improving diagnostic accuracy in clinical practice (particularly at the early stage of the disease), improving the enrollment in clinical trials, and facilitating research with validation of diagnostic markers. A validation exercise on the new criteria in a prospective clinicopathological study is planned to determine their diagnostic accuracy. Importantly, the number of research biomarkers that will turn out to be reliable and consistent in clinical settings to support a clinical diagnosis of MSA or prodromal MSA will grow in the future. Thus, criteria refinement will be needed when more evidence becomes available.