Diagnostic criteria for clinically established and clinically probable MSA.
The Movement Disorder Society Criteria for diagnosis of multiple system atrophy (MDS MSA criteria) are developed to address poor sensitivity at early disease stages of the previous set of diagnostic criteria (Gilman et al. 2008) and their overall suboptimal accuracy. The MDS MSA criteria are designed for clinical practice, for the inclusion of patients in clinical trials, and for research purposes. It has four levels of diagnostic accuracy: neuropathologically established MSA, clinically established MSA, clinically probable MSA and possible prodromal MSA. Neuropathologically established MSA is made on postmortem examination.
Clinically established and clinically probable MSA require a combination of core clinical features (autonomic failure, parkinsonism and cerebellar syndrome), supportive motor and non-motor features, brain MRI findings and an absence of exclusion criteria. These categories should be divided into MSA-parkinsonian (MSA-P) and MSA-cerebellar (MSA-C) depending on the predominant motor phenotype. Core clinical features of clinically probable MSA are more sensitive and usually manifest earlier compared to the core features of clinically established MSA (see bold in table). While autonomic failure is a mandatory criterion for clinically established MSA diagnosis, at least two of autonomic failure, parkinsonism and cerebellar syndrome in any combination, including parinsonisam and ataxia without autonomic failure, allow for the diagnosis of clinically probable MSA. Clinically established MSA requires one brain MRI marker of atrophy or diffusivity changes in the putamen or infratentorial structures suggestive of MSA, while no MRI markers are required for the diagnosis of clinically probable MSA.
Possible prodromal MSA is a research category designed to capture patients at their early disease stage. Patients in this category are those with isolated autonomic failure and REM sleep behavior disorder, subtle motor signs and an absence of exclusion criteria. Most supportive biomarkers were not included in the new criteria due to their still limited availability and a need for validation. However, we encourage clinicians to investigate their presence in patients with all MSA categories whenever available so that more data will be available in the future.
Supportive biomarkers suggestive of MSA but not required for the MSA diagnosis with operationalized definitions (applicable for all clinical MSA diagnostic categories if not indicated otherwise)
|Suppotive biomarker||Operationalized definition|
||Structural brain MRI (1.5 or 3.0 T) analysis is based on visual inspection by a neuroradiologist who has explicitly to be advised by a movement disorder specialist to evaluate these features. Diffusion brain MRI analysis is based on quantitative assessments by a neuroradiologist who has explicitly to be advised by a movement disorder specialist to evaluate these features.|
For MSA-P hypometabolism of:
For MSA-C hypometabolism of:
|Based on visual inspection by a nuclear medicine specialist.|
|Normal cardiac sympathetic imaging (123I-MIBG-scintigraphy)**||Normal heart/mediastinum ratio 4 hours after intravenous injection of 123I-MIBG, as assessed by a nuclear medicine specialist. Medications affecting noradrenaline transporter and vesicular storage, structural heart disease and common causes of small fiber neuropathies, such as diabetes mellitus that may affect the findings must be excluded.|
|Polysomnography proven REM sleep behavior disorder**||According to American Academy of Sleep Medicine's International Classification of Sleep Disorders, Third Edition (ICSD-3).|
|Supine plasma norepinephrine level >100 pg/ml associated with neurogenic OH||Using high-performance liquid chromatography with electrochemical detection after 10 minutes lying supine associated with neurogenic OH.|
|Detrusor hyperactivity with impaired contraction or detrusor sphincter dyssynergia on urodynamic testing||Synchronous contraction of detrusor and urethral sphincter during voiding on urodynamic study.|
|Unexplained abnormal sphincter EMG||Concentric needle EMG of external anal sphincter demonstrating more than 20% of motor unit potentials (MUPs) having a duration >10 ms, or the average duration of MUPs >10 ms. Recorded MUPs should be analysed manually to include late components. Similar changes of chronic reinnervation may be seen with cauda equina injury, following pelvic surgery and obstetric pelvic floor tears and other neurodegenerative disorders (such as PSP and long standing PD).|
|CSF α-synuclein oligomers detected by PMCA or RT-QUIC||Detected by PMCA or RT-QUIC.|
|Increased plasma or CSF NfL detected by ELISA||Detected by ELISA or SIMOA.|
* Applicable for possible prodromal MSA
# Division into motor subtypes is not applicable for possible prodromal MSA category
** Applicable for clinically established and clinically probable MSA
1. Presence of autonomic dysfunction?
Autonomic dysfunction defined as (at least one is required)
• unexplained voiding difficulties with post void urinary residual volume > 100 ml
• unexplained urinary urge incontinence
• neurogenic OH (≥20 mmHg systolic and/or ≥10 mmHg diastolic blood pressure drop) within 3 minutes of standing or head-up tilt test