Multiple system atrophy (MSA) is a progressive neurodegenerative disorder with a mean survival of 6-10 years. Early and accurate diagnosis is crucial for patient management and for the development of disease-modifying therapies. However, the diagnosis of MSA at the early stage reaches a low 18% of patients, and this is largely due to limitations in the current clinical criteria. Typically for MSA diagnosis, a patient should have both motor symptoms (poorly L-Dopa-responsive parkinsonism and/or cerebellar dysfunction) and autonomic dysfunctions. These criteria are not only vague but also not specific of MSA, and in many patients motor and autonomic symptoms do not develop simultaneously. Also important, recent studies have shown that patients with MSA can present with a wider range of clinical features including some previously considered too atypical for MSA. We have asked two experts in this field, Drs. Kaufmann and Watanabe, to discuss the current state of the art in MSA diagnosis.
What are the problems with the current clinical diagnostic criteria of MSA?
The second consensus statement proposed in 2008 required strictly defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia for the diagnosis of probable MSA. The clinical diagnosis of possible MSA requires a sporadic, progressive, adult-onset disease with either parkinsonism or cerebellar ataxia and at least one feature suggesting dysautonomia plus one additional supporting feature. The statement also defined the supporting (red flags) and non-supporting features for MSA diagnosis. However, improvements in early diagnosis of MSA remained limited (sensitivity of first clinical visit reaching 41% of possible MSA based on the second consensus criteria compared to 28% based on the first consensus criteria). Furthermore, only 18% of patients fulfilled the criteria for probable MSA at the first clinical visit.
The median time from the presentation of the initial symptom to combined motor and autonomic dysfunction in MSA (probable MSA) is 2 years, but ranges from 1 to 19 years. Therefore, ,many patients with MSA who present isolated autonomic failure, parkinsonism, or cerebellar ataxia during the early phase of illness will not be diagnosed as “possible” or “probable” based on the current diagnostic criteria. In addition, the high positive predictive value (86-100%) of MSA patients who meet the “probable” criteria was contradicted by Koga et al.1 showing that 38% of such cases changed the final diagnosis at autopsy. The presence of autonomic failure and cerebellar ataxia were the leading causes of misdiagnosis of dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP), respectively. On the other hand, symptoms of DLB and PSP such as dementia, hallucinations, and vertical gaze palsy may be observed in MSA patients. Consequently, a revision of the second consensus criteria for the early and clinically definitive diagnosis of MSA is urgently needed.
The current clinical diagnostic criteria for multiple system atrophy are very good but they could be improved upon. At the moment, the biggest limitation is our inability to diagnose the disease early on in its clinical course. It is widely agreed that this is an important shortcoming if we are going to test potential neuroprotective or disease-modifying drugs.
Another useful addition to the diagnostic criteria could be a higher level of certainty in the diagnosis while the patient is alive. Currently, definite MSA requires neuropathological confirmation. Our understanding of the disease has increased and delineating criteria for clinically diagnosed definite MSA should be possible. This could facilitate communication with patients and would be helpful for adequate recruitment and interpretation of the results of clinical trials.
Even when the disease is advanced, there is a currently marked difference in diagnostic accuracy between specialized centers and general neurology or primary care clinics. This gap could be reduced and the level of diagnostic certainty of specialized centers increased with clinically diagnosed definite MSA criteria.
Have we made progress in our understanding of MSA and biomarker identification?
Our understanding of the intrinsic mechanism of MSA has steadily improved. Relocation of phosphoprotein-25a (p25a) from the myelin sheath to the oligodendroglial cell soma followed by formation of cytoplasmic p25α inclusions can be an early event in patients with MSA. Expression, aggregation and propagation of α-synuclein (α-syn) are considered to be closely associated with disease onset and progression. Neuroinflammation, reduced glial cell line-derived neurotrophic factor expression, autophagy disturbance, and mitochondrial failure can also play a critical role in the pathogenesis of MSA. Functionally impaired variants of COQ2 is associated with an increased risk of MSA predominated cerebellar ataxia (MSA-C) in patients of East Asian ancestry. Based on these findings, several disease modifying therapies such as autologous mesenchymal stem cells (NCT02315027), myeloperoxidase inhibitors for ameliorating microglial activation (NCT02388295), and two vaccines (PD01A and PD03A) against α-synuclein (NCT02270489) have been conducted.
Regarding biomarkers, olfactory function test and 123I-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy can be valuable to differentiate Parkinson’s disease (PD) and DLB from MSA in the early stages. Diffusion-weighted MRI and individual automated volumetry can be a good candidate for a diagnostic marker of MSA. Several candidate PET radiotracers for aggregated α-syn imaging have been under development for years. Other markers may be found with skin biopsy (α-syn detection), retinal nerve fiber layer thickness, and blood and cerebrospinal fluid substances (neurofilament light chain, catecholamine metabolite). Disease-related proteins such as total α-synuclein, DJ-1, amyloid beta and total tau may also show some abnormalities in MSA. However, there are still no reliable biomarkers for the diagnosis of MSA
While blood and CSF based biomarkers are still not satisfactory, there has been significant progress in brain imaging and clinical phenotype. A number of brain MRI abnormalities have excellent specificity to support the diagnosis of MSA in clinically advanced disease but, unfortunately, no abnormalities have yet been identified for early-stage disease..
I have been impressed with the usefulness of smell testing in the differential diagnosis between MSA and the Lewy body disorders. In a patient with parkinsonism, preserved smell strongly support the diagnosis of MSA. These and other data were not available at the time of the current consensus and should be discussed.
Do we need ‘prodromal MSA’ or ‘mono-system atrophy’ criteria?
In 2015, the International Parkinson and Movement Disorder Society (MDS) proposed both clinical diagnostic criteria for PD and research criteria for prodromal PD. Prior to defining these criteria, the MDS task force discussed the issue of PD redefinition and provided key points to establish diagnostic criteria: 1) overemphasis on avoiding false-positive diagnoses can be associated with missing many patients with true PD, but overemphasis on including all PD patients leads to false-positive diagnoses. 2) The importance of false negatives versus false positives varies depending on the purpose for which criteria are applied. 3) Criteria should incorporate different levels of certainty, delineated as “clinical PD (highly specific, but not necessarily sensitive or representative) and “possible PD” (balancing specificity and sensitivity).
These considerations seem to be also important for developing improved MSA diagnostic criteria, and apply to the criteria for clinical and prodromal MSA (or isolated motor or autonomic involvement phase - mono system atrophy). Making an early diagnosis of MSA can be as challenging as diagnosing prodromal PD. Kaufmann et al.2 demonstrated that 6 of 74 patients with pure autonomic failure convert to MSA during the follow up period. This article also showed that the combination of olfactory function and plasma Noradrenaline (NA) levels successfully classified PD/DLB (impaired olfaction, tended to have lower NA levels), Pure autonomic failure (PAF) (normal olfaction and lower NA levels), and MSA (normal olfaction and tended to have plasma NA levels that were not low). 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy can also differentiate MSA from PD, DLB, and PAF. Patients with isolated cerebellar ataxia and isolated parkinsonism are more frequently seen in Asian countries and Western countries, respectively. A significant minority of patients with idiopathic REM sleep behavior disorder also is thought to represent a prodromal MSA.
Large collaborative and prospective observational studies including clinical examination, brain MRI, and blood, olfactory, autonomic, and genetic tests will help differentiate early MSA from other adult onset conditions, i.e. sporadic cerebellar ataxias, PD, PSP, and DLB. Other disorders that can mimick MSA features are immune, infectious, tumoral, and vascular lesions, and hereditary disorders such as spinocerebellar ataxias and fragile X–associated tremor ataxia syndrome.
Diagnostic criteria for prodromal MSA would be extremely useful. There is no doubt that the neurodegenerative process in all synucleinopathies begins way before abnormal motor findings are recognized clinically. Prodromal research criteria have recently been defined for PD, and we should attempt to do the same for MSA. Because MSA is a rare disease and the available data for prevalence and incidence of the disease is scant, this task poses a big challenge. But we need to start with the data we have. Interestingly, several prodromal features are common in all synucleinopathies while others appear to be distinct for MSA. For example, a male patient with neurogenic orthostatic hypotension, neurogenic bladder and REM sleep behavior disorder has a high likelihood of having prodromal PD but if his sense of smell is preserved he may be more likely to have MSA. In that same patient, preserved sympathetic innervation of the heart, as shown by a higher heart rate for example, may similarly tilt the risk towards MSA. Data from urology and ENT clinics also suggest particular findings in patients with early MSA. The specificity of some of these findings may be low but still worthwhile investigating.
Defining possible prodromal MSA as a research category may increase awareness of the disease in urology, cardiology, and ENT clinics. Hopefully, it will stimulate research and clinical recognition of MSA.
1. Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, et al. When DLB, PD, and PSP masquerade as MSA An autopsy study of 134 patients. Neurology. 2015;85:404-12.
2. Kaufmann H, Norcliffe-Kaufmann L, Palma JA, Biaggioni I, Low PA, Singer W, et al; Autonomic Disorders Consortium. Natural history of pure autonomic failure: A United States prospective cohort. Ann Neurol. 2017;81:287-297.