Criteria For Multiple System Atrophy Research Articles

Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.

Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials.

Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts.

Two patients of immunotherapy-responsive autoimmune cerebellar ataxia fulfilled with criteria of multiple system atrophy

We report two patients with autoimmune cerebellar ataxia who fulfilled the diagnostic criteria of multiple system atrophy (MSA) and responded to immunotherapies. Patient 1 was a 72-year-old man who was diagnosed with clinically probable MSA according to Movement Disorder Society criteria. Patient 2 was a 68-year-old man who was diagnosed with clinically established MSA according to Movement Disorder Society criteria. Both patients showed cerebellar ataxia, autonomic dysfunction, and pyramidal tract signs; however, they also had atypical clinical features. Patient 1 exhibited self-‍limiting mild improvement of clinical symptoms and had inflammatory findings in his cerebrospinal fluid. Patient 2 showed a rapidly progressive clinical course. We therefore examined anti-neuronal antibodies using tissue-based immunohistochemical assays with frozen rat cerebellum sections. We detected autoantibodies that mainly reacted with the cytoplasm of Purkinje cells. The two patients then underwent immunotherapies, which led to substantial improvements in their clinical symptoms. Our findings indicate that some patients with autoimmune cerebella ataxia have clinical features that resemble MSA, and respond well to immunotherapies.

Diagnostic utility of movement disorder society criteria for multiple system atrophy.

The 2008 criteria for the diagnosis of multiple system atrophy (MSA) has been widely used for more than 10 years, but the sensitivity is low, particularly for patients in the early stage. Recently, a new MSA diagnostic criteria was developed. The objective of the study was to assess and compare the diagnostic utility of the new movement disorder society (MDS) MSA criteria with the 2008 MSA criteria. This study included patients diagnosed with MSA between January 2016 and October 2021. All patients underwent regular face-to-face or telephonic follow-ups every year until October 2022. A total of 587 patients (309 males and 278 females) were retrospectively reviewed to compare the diagnostic accuracy of the MDS MSA criteria to that of the 2008 MSA criteria (determined by the proportion of patients categorized as established or probable MSA). Autopsy is the gold standard diagnosis of MSA, which is not available in clinical practice. Thus, we applied the 2008 MSA criteria at the last review as the reference standard. The sensitivity of the MDS MSA criteria (93.2%, 95% CI = 90.5-95.2%) was significantly higher than that of the 2008 MSA criteria (83.5%, 95% CI = 79.8-86.6%) (P < 0.001). Additionally, the sensitivity of the MDS MSA criteria was maintained robustly across different subgroups, defined by diagnostic subtype, disease duration, and the type of symptom[s] at onset. Importantly, the specificities were not significantly different between the MDS MSA criteria and the 2008 MSA criteria (P > 0.05). The present study demonstrated that the MDS MSA criteria exhibited good diagnostic utility for MSA. The new MDS MSA criteria should be considered as a useful diagnostic tool for clinical practice and future therapeutic trials.

Redefining Bradykinesia.

Redefining Bradykinesia.

New MDS Criteria for the Diagnosis of Multiple System Atrophy: Overview and Genetic Viewpoint

A new diagnostic criteria for multiple system atrophy, "The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy (MSA)", has been proposed. Under the new criteria, new categories of "clinically established MSA," "clinically probable MSA," and "possible prodromal MSA" have been introduced. The new diagnostic criteria is expected to facilitate early and accurate diagnosis of MSA in clinical practice for MSA patients and clinical trials for MSA. In the diagnostic criteria, "A sporadic, progressive adult (>30 years) onset disease" is described as an "essential feature of MSA," and thus attention to familial occurrence of MSA is not included. Familial occurrence of MSA, however, was recognized first in Japan, and later in the world. We have witnessed discoveries of numerous genes underlying other neurodegenerative diseases, including Parkinson disease, and therefore application of molecular genetics research for MSA is highly expected to contribute to elucidating the molecular basis of MSA. Although the new diagnostic criteria is designed to facilitate early and accurate diagnosis of sporadic MSA, we simultaneously need to pay attention to familial occurrence of MSA and promotion of molecular genetics research of MSA.

New MDS Criteria for the Diagnosis of Multiple System Atrophy: How to Use in Clinical Practice and Clinical Trials

The newly revised diagnostic criteria for multiple system atrophy (MSA) have reduced the criteria for diagnosing orthostatic hypotension compared to the conventional diagnostic criteria, but require tests such as MRI and residual urine measurement. Under the new diagnostic criteria, cases that were previously classified as possible MSA with low diagnostic accuracy may become clinically established with higher diagnostic accuracy. However, examination of the cohort treated in our establishment showed that there were cases in which the diagnostic criteria could not be applied when the symptoms and test items necessary for diagnosis were not confirmed. In clinical trials, clinically established or clinically probable MSA are targeted for interventional studies, and possible prodromal MSA are considered to be more important for observational studies. In the future, it will be necessary to confirm the diagnostic accuracy pathologically, accumulate evidence from various clinical tests that are listed as supportive biomarkers, and to develop more useful diagnostic criteria.

Pathological Validation of the MDS Criteria for the Diagnosis of Multiple System Atrophy.

The recent International Parkinson and Movement Disorder Society diagnostic criteria for multiple system atrophy (MDS-MSA) have been developed to improve diagnostic accuracy although their diagnostic properties have not been evaluated. The aims were to validate the MDS-MSA diagnostic criteria against neuropathological diagnosis and compare their diagnostic performance to previous criteria and diagnosis in clinical practice. Consecutive patients with sporadic, progressive, adult-onset parkinsonism, or cerebellar ataxia from the Queen Square Brain Bank between 2009 and 2019 were selected and divided based on neuropathological diagnosis into MSA and non-MSA. Medical records were systematically reviewed, and clinical diagnosis was documented by retrospectively applying the MDS-MSA criteria, second consensus criteria, and diagnosis according to treating clinicians at early (within 3 years of symptom onset) and final stages. Diagnostic parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as gold standard and compared between different criteria. Three hundred eighteen patients (103 MSA and 215 non-MSA) were included, comprising 248 patients with parkinsonism and 70 with cerebellar ataxia. Clinically probable MDS-MSA showed excellent sensitivity (95.1%), specificity (94.0%), and accuracy (94.3%), although their sensitivity at early stages was modest (62.1%). Clinically probable MDS-MSA outperformed diagnosis by clinicians and by second consensus criteria. Clinically established MDS-MSA showed perfect specificity (100%) even at early stages although to the detriment of low sensitivity. MDS-MSA diagnostic accuracy did not differ according to clinical presentation (ataxia vs. parkinsonism). MDS-MSA criteria demonstrated excellent diagnostic performance against neuropathological diagnosis and are useful diagnostic tools for clinical practice and research. © 2023 International Parkinson and Movement Disorder Society.

Comparison of the second consensus statement with the movement disorder society criteria for multiple system atrophy: A single-center analysis

IntroductionThis study aimed at comparing the differences between the second consensus statement and Movement Disorder Society (MDS) criteria for Multiple System Atrophy (MSA) in a single Chinese cohort. MethodsWe retrospectively reviewed 73 patients with MSA over the past five years. They were categorized as patients with probable and possible MSA according to the second consensus statement in addition to clinically established and clinically probable MSA according to the MDS criteria. The core clinical, supportive clinical, and imaging features were analyzed and compared between the two MSA subtypes. ResultsA total of 40 patients with MSA-P and 33 patients with MSA-C were included in this study. Approximately 78.7% of the category of probable patients in the second consensus statement can be categorized as clinically established MSA in the MDS criteria and five patients with non-supporting features in the second consensus statement criteria can be diagnosed as clinically probable MSA in the MDS criteria. “Rapid progression” and “moderate to severe postural instability” within three years of motor onset dominated among the supportive features. Approximately 78.9% of patients possessed at least one imaging marker with predominant signal decrease of putamen on iron-sensitive sequences (38.0% of patients). Twenty-two patients could not be diagnosed as clinically established MSA mainly due to the lack of supportive or imaging features. ConclusionsA high degree of agreement was noticed between the two criteria sets. The supportive and imaging features played important role in the diagnosis of MSA and affected the diagnostic level in the current criteria.

The Non-motor Symptoms, Disability Progression, and Survival Analysis of Atypical Parkinsonism: Case Series from Eastern India and Brief Review of Literature

Objective The objectives of this study are (1) to describe the non-motor profile, the motor disability progression, and survival analysis of atypical parkinsonism in a tertiary care hospital of eastern India and (2) to elucidate the neurocircuitry and the putative substrates responsible for non-motor manifestations. Methods In this prospective observational study, patients were diagnosed based on Consensus Criteria for Progressive Supranuclear Palsy (PSP), The Fourth Consensus Report of the Dementia with Lewy Body (DLBD) Consortium 2017, The Autonomic Neuroscience 2018 Criteria for Multiple System Atrophy (MSA), and Armstrong 2013 Criteria for Corticobasal Degeneration (CBD). Disease severity was assessed at baseline and 6 months of follow-up using the Unified Parkinson's Disease Rating Scales (UPDRS). For PSP and MSA, the PSP-Clinical Deficits Scale (PSP-CDS) and the Unified MSA Rating Scale (UMSARS), respectively, were used. Cox regression analysis and the hazard ratio were calculated. Results Out of 27 patients, the diagnosis was probable PSP in 12, probable MSA in 7, probable CBD in 5, and probable DLBD in 3. Non-motor symptoms were highly prevalent across all subtypes. Motor disability progression as assessed by UPDRS parts 2 and 3 showed significant deterioration over 6-month follow-up across all groups ( p < 0.05). Disease progression assessed by PSP-CDS and UMSARS over 6 months was significant ( p < 0.05). One PSP and two MSA patients died during a 6-month follow-up period. The hazard ratio in MSA was 3.5 (95% confidence interval: 0.31–0.38) with p = 0.306. Conclusion Atypical parkinsonian disorders are rare, and usually more severe than idiopathic parkinsonism. As no definitive treatment is available, symptomatic management involving a multidisciplinary team approach must be prioritized.

Diagnosing multiple system atrophy at the prodromal stage.

Identifying individuals at the earliest disease stage becomes crucial as we aim to develop disease-modifying treatments for neurodegenerative disorders. Prodromal diagnostic criteria were recently developed for Parkinson's disease (PD) and are forthcoming for dementia with Lewy bodies (DLB). The latest 2008 version of diagnostic criteria for multiple system atrophy (MSA) have improved diagnostic accuracy in early disease stages compared to previous criteria, but we do not yet have formal criteria for prodromal MSA. Building on similar approaches as for PD and DLB, we can identify features on history-taking, clinical examination, and ancillary clinical testing that can predict the likelihood of an individual developing MSA, while also distinguishing it from PD and DLB. The main clinical hallmarks of MSA are REM sleep behavior disorder (RBD) and autonomic dysfunction (particularly orthostatic hypotension and urogenital symptoms), and may be the primary means by which patients with potential prodromal MSA are identified. Preserved olfaction, absence of significant cognitive deficits, urinary retention, and respiratory symptoms such as stridor and respiratory insufficiency can be clinical features that help distinguish MSA from PD and DLB. Finally, ancillary test results including neuroimaging as well as serological and cerebrospinal fluid (CSF) biomarkers may lend further weight to quantifying the likelihood of phenoconversion into MSA. For prodromal criteria, the primary challenges are MSA's lower prevalence, shorter lead time to diagnosis, and strong overlap with other synucleinopathies. Future prodromal criteria may need to first embed the diagnosis into a general umbrella of prodromal alpha-synucleinopathies, followed by identification of features that suggest prodromal MSA as the specific cause.

A critique of the second consensus criteria for multiple system atrophy.

A critique of the second consensus criteria for multiple system atrophy.

Multiple system atrophy mimicked by multi-organ pathology

Both multiple system atrophy and Parkinson’s disease may present with parkinsonism and autonomic dysfunction. We describe a patient who initially met the diagnostic criteria for multiple system atrophy and had...

Senile Depression with Somatization Symptoms and Insomnia is Diagnosed as Multiple System Atrophy: A Case Report.

SummaryPatients who have senile depression with somatization symptoms are commonly encountered in clinical practice. The present case reports on a patient with senile depression who was repeatedly hospitalized and had somatic symptoms. Although the patient recovered after the first hospitalization, she suffered from a relapse one year later. As we followed up, due to the neurological findings and the response to treatment, we found that the patient is in line with the diagnoistic criteria for multiple system atrophy (MSA). The process of diagnosis and treatment of this case reminds us that clinicians need to consider differential diagnosis for refractory senile depression, especially in those patients with prominent somatization. In this case, rapid eye movement sleep behavior disorder (RBD) serves as a characteristic feature of the organic mental disorder.

Brain structural profile of multiple system atrophy patients with cognitive impairment.

Current consensus diagnostic criteria for multiple system atrophy (MSA) consider dementia a non-supporting feature, although cognitive impairment and even frank dementia are reported in clinical practice. Mini-Mental State Examination (MMSE) is a commonly used global cognitive scale, and in a previous study, we established an MSA-specific screening cut-off score <27 to identify cognitive impairment. Finally, MSA neuroimaging findings suggest the presence of structural alterations in patients with cognitive deficits, although the extent of the anatomical changes is unclear. The aim of our multicenter study is to better characterize anatomical changes associated with cognitive impairment in MSA and to further investigate cortical and subcortical structural differences versus healthy controls (HC). We examined retrospectively 72 probable MSA patients [50 with normal cognition (MSA-NC) and 22 cognitively impaired (MSA-CI) based on MMSE<27] and compared them to 36 HC using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to HC, MSA patients showed widespread cortical (bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white-matter alterations. However, MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These results suggest only a marginal contribution of cortical pathology to cognitive deficits. We believe that cognitive dysfunction is driven by focal fronto-striatal degeneration in line with the concept of "subcortical cognitive impairment".

Highly specific radiographic marker predates clinical diagnosis in progressive supranuclear palsy

IntroductionThe diagnosis of progressive supranuclear palsy is often challenging early in the course of the disease, when clinical signs of the condition may be less apparent and patients do not clearly meet diagnostic criteria. In this study, we examine a potential radiographic marker in progressive supranuclear palsy, and assess the timing of its presence in relation to diagnosis. MethodsA retrospective review of patients fulfilling clinical research criteria for multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy (total n = 75) was performed. Midbrain and pontine diameters, and the midbrain to pons ratio were calculated by a neuroradiologist blinded to the clinical diagnosis. The timing of the presence of a midbrain to pons ratio of less than or equal to 0.52 was assessed in the progressive supranuclear palsy group in reference to the time of diagnosis. ResultsThe midbrain to pons ratio was significantly reduced in the progressive supranuclear palsy cohort (p < 0.0001), and a midbrain to pons ratio of less than or equal to 0.52 was 100% specific for progressive supranuclear palsy. This radiologic sign predated the clinical diagnosis of progressive supranuclear palsy by a mean of 15 months (range 1–47 months) in 14 of 17 (82%) of patients in whom it was found. ConclusionsThe midbrain to pons ratio is an easily applied and highly specific tool in the diagnosis of progressive supranuclear palsy, and is frequently present before the diagnosis is made.

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The diagnosis of progressive supranuclear palsy is often challenging early in the course of the disease, when clinical signs of the condition may be less apparent and patients do not clearly meet diagnostic criteria. In this study, we examine a potential radiographic marker in progressive supranuclear palsy, and assess the timing of its presence in relation to diagnosis.A retrospective review of patients fulfilling clinical research criteria for multiple system atrophy, Parkinson's disease, and progressive supranuclear palsy (total n = 75) was performed. Midbrain and pontine diameters, and the midbrain to pons ratio were calculated by a neuroradiologist blinded to the clinical diagnosis. The timing of the presence of a midbrain to pons ratio of less than or equal to 0.52 was assessed in the progressive supranuclear palsy group in reference to the time of diagnosis.The midbrain to pons ratio was significantly reduced in the progressive supranuclear palsy cohort (p < 0.0001), and a midbrain to pons ratio of less than or equal to 0.52 was 100% specific for progressive supranuclear palsy. This radiologic sign predated the clinical diagnosis of progressive supranuclear palsy by a mean of 15 months (range 1–47 months) in 14 of 17 (82%) of patients in whom it was found.The midbrain to pons ratio is an easily applied and highly specific tool in the diagnosis of progressive supranuclear palsy, and is frequently present before the diagnosis is made.

Multiple System Atrophy and Repeat Expansions inC9orf72—Reply

In Reply We appreciate the comments by Schottlaender and colleagues concerning our article1 published in JAMA Neurology. We agree that the importance of our article was to highlight the variable phenotypes that are associated with C9orf72 expansions. To date, the reported C9orf72 expansion– associated phenotypes have been frontotemporal dementia, amyotrophic lateral sclerosis (ALS), frontotemporal dementia/ ALS, Huntington disease–like disorders,2 psychiatric disorders, dementia of Lewy bodies,3 parkinsonism,4 and multiple system atrophy (MSA).1 The case presented in our article met clinical, not pathological, criteria for MSA, which included dysautonomia (neurogenic bladder and orthostatic hypotension), cerebellar syndrome (dysarthria, imbalance, and ataxic gait), parkinsonism,5 and the hot-cross-bun sign in the brain imaging. Especially early in disease progression, the symptoms of MSA may overlap with certain inherited conditions such as Fragile X–associated tremor and ataxia syndrome and spinocerebellar ataxias. In fact, we reported a case with ataxia and spinocerebellar ataxia type 2 repeat expansions, who also had a family history of ALS.6 These disorders differ pathologically from MSA yet may involve the same brain areas, leading to similar clinical presentations. We agree that autopsy will be very helpful to delineate the ultimate pathological diagnosis in this case. To our knowledge, all pathology of C9orf72 expansions showed the characteristic ubiquitin, p62-positive, TDP-43–negative neuronal cytoplasmic and intranuclear inclusions. Therefore, it is reasonable to expect that both the patient and her brother could have typical C9orf72 pathology. Another possibility is the coexistence of synucleinopathy with C9orf72 expansions because MSA synucleinopathy has been reported to occur with other neurodegenerative changes such as tau pathology.5 Until we can confirm the pathology of MSA with C9orf72 expansions, clinicians should be aware that many possible clinical phenotypes are associated with C9orf72 expansions and should consider genetic testing in the presence of family history of a related neurologic disease.

Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group.

Consensus diagnostic criteria for multiple system atrophy consider dementia as a nonsupporting feature, despite emerging evidence demonstrating that cognitive impairments are an integral part of the disease. Cognitive disturbances in multiple system atrophy occur across a wide spectrum from mild single domain deficits to impairments in multiple domains and even to frank dementia in some cases. Frontal-executive dysfunction is the most common presentation, while memory and visuospatial functions also may be impaired. Imaging and neuropathological findings support the concept that cognitive impairments in MSA originate from striatofrontal deafferentation, with additional contributions from intrinsic cortical degeneration and cerebellar pathology. Based on a comprehensive evidence-based review, the authors propose future avenues of research that ultimately may lead to diagnostic criteria for cognitive impairment and dementia associated with multiple system atrophy.

Дифференциальная диагностика болезни Паркинсона и мультисистемной атрофии

Целью нашей работы было выделение и описание ключевых дифференциально-диагностических признаков и критериев мультисистемной атрофии и болезни Паркинсона с целью улучшения диагностики и дифференциальной диагностики этих заболеваний. Обследовано 205 больных с идиопатической болезнью Паркинсона и 17 больных мультисистемной атрофией. Тяжесть заболевания в группе больных мультисистемной атрофией была значительно выше, чем у пациентов с болезнью Паркинсона. Падения, застывания при ходьбе, нарушения глотания, вегетативные расстройства, интеллектуальные нарушения и депрессия встречались достоверно чаще в группе больных мультисистемной атрофией по сравнению с группой больных паркинсонизмом. В отличие от болезни Паркинсона, при которой в подавляющем большинстве случаев (97,84 %) наблюдался отличный, хороший или умеренный эффект противопаркинсонических препаратов, у большинства больных мультисистемной атрофией (73,33 %) наблюдался только незначительный терапевтический эффект. Быстро прогрессирующие вегетативные расстройства (не связанные с какой-либо сопутствующей патологией), развившиеся незадолго (1–2 года) до появления паркинсонизма, а также начало заболевания с нарушения постуральных рефлексов могут быть одними из дифференциальных признаков мультисистемной атрофии.