Diagnosis Of Multiple System Atrophy Research Articles

Differential diagnosis of multiple system atrophy with predominant parkinsonism and Parkinson's disease using neural networks

Differential diagnosis between Parkinson's disease (PD) and atypical parkinsonism, such as multiple system atrophy (MSA), can be difficult, especially in the early stages of the disease. Deep learning using neural networks (NNs) makes possible the prediction of the diagnosis using various types of biomarkers, unlike conventional linear statistics. We aimed to differentiate the Parkinson's variant of MSA (MSA-P) from PD both in the early stages by clinical utilization of NN analyses before the hot cross-bun and putaminal rim imaging features of MSA appeared. Analysis by NN involved the data of voxel-based morphometry (VBM) that indicate morphological changes and magnetic resonance spectroscopy (MRS) that indicate qualitative changes. VBM analysis showed that compared with PD patients, MSA-P patients showed atrophy in the superior cerebellar peduncle, middle cerebellar peduncle, cerebellar hemisphere, pons, midbrain, and putamen, but not in the globus pallidus. Proton MRS on the globus pallidus in the diseased hemisphere, lacking atrophy as observed with VBM, revealed decreased neurons and gliosis in both groups. Clinical differentiation of MSA-P from PD using NN analysis, involved measuring the prediction potential using the area under the receiver operator characteristic (ROC) curves (AUC). Using both VBM and MRS data, NNs contributed adequately to the clinical diagnosis.

Morphometric MRI profiles of multiple system atrophy variants and implications for differential diagnosis.

BackgroundManual width measurements of the middle cerebellar peduncle on MRI were shown to improve the accuracy of an imaging‐guided diagnosis of multiple system atrophy (MSA). Recently, automated volume segmentation algorithms were able to reliably differentiate patients with Parkinson's disease (PD) and the parkinsonian variant of MSA. The objective of the current study was to integrate probabilistic information of the middle cerebellar peduncle into an existing MRI atlas for automated subcortical segmentation and to evaluate the diagnostic properties of the novel atlas for the differential diagnosis of MSA (parkinsonian and cerebellar variant) versus PD.MethodsThree Tesla MRI scans of 48 healthy individuals were used to establish an automated whole‐brain segmentation procedure that includes the volumes of the putamen, cerebellar gray and white matter, and the middle cerebellar peduncles. Classification accuracy of segmented volumes were tested in early‐stage MSA patients (18 MSA‐parkinsonism, 13 MSA‐cerebellar) and 19 PD patients using a C4.5 classifier.ResultsPutaminal and infratentorial atrophy were present in 77.8% and 61.1% of MSA‐parkinsonian patients, respectively. Four of 18 MSA‐parkinsonian patients (22.2%) had infratentorial atrophy without evidence of putaminal atrophy. Infratentorial atrophy was present in all MSA‐cerebellar patients, with concomitant putaminal atrophy in 46.2% of these cases. The diagnostic algorithm using putaminal and infratentorial volumetric information correctly classified all PD patients and 96.8% of MSA patients.ConclusionsThe middle cerebellar peduncle was successfully integrated into a subcortical segmentation atlas, and its excellent diagnostic accuracy outperformed existing volumetric MRI processing strategies in differentiating MSA patients with variable atrophy patterns from PD patients. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The severity of motor dysfunctions and urinary dysfunction is not correlated in multiple system atrophy

ObjectiveAlthough it is well known that patients with multiple system atrophy (MSA) cerebellar dominant type (MSA-C) show severe autonomic dysfunction, the relationship between autonomic and motor dysfunction remains uncertain. Previously we reported that severe urinary voiding dysfunction is useful in differential diagnosis of MSA and other diseases. Herein, we aimed to clarify the relationship between the severity of motor dysfunctions and urinary dysfunction. MethodThis study is a retrospective review of 46 patients with MSA-C diagnosed according to Gilman's second consensus criteria. The severity of motor dysfunctions was evaluated using International Cooperative Ataxia Rating Scale (ICARS). Urinary voiding dysfunction was evaluated by measuring post-void residual (PVR). The mean duration of motor unit potentials in external anal sphincter muscles on electromyography, which represents the severity of neurodegeneration in Onuf's nucleus, was also examined. ResultsThe mean age of patients was 63.8 ± 8.2 years and mean disease duration was 3.0 ± 1.9 years. The mean ICARS score was 40.1 ± 14.7. The mean PVR was 119.1 ± 102 ml and the mean duration of motor unit potentials (MUPs) in anal sphincter electromyography was 9.2 ± 2.2 ms. The correlation coefficient between ICARS and PVR was 0.093 (p = .539), and between ICARS and mean duration of MUPs was 0.105 (p = .811). A significant positive correlation (r = 0.296, p = .005) was noted between PVR and the mean duration of MUP. ConclusionMotor and urinary dysfunctions were not correlated in MSA-C.

Chapter 28 - Clinical neurophysiology of multiple system atrophy

Multiple system atrophy (MSA) is an adult-onset, rapidly progressive neurodegenerative syndrome. The diagnosis of MSA is primarily clinical. Neurophysiologic studies can provide important clues to the diagnosis of MSA and differentiate it from other neurodegenerative diseases especially when the clinical picture is unclear. This chapter reviews common and less common neurophysiological studies useful in the diagnosis of MSA.

Arrested Progression of Symptoms of a Patient Diagnosed with Multiple System Atrophy for a Period Over 6 Months

Arrested Progression of Symptoms of a Patient Diagnosed with Multiple System Atrophy for a Period Over 6 Months

Brain morphological alteration and cognitive dysfunction in multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease in adults, manifesting various clinical symptoms including autonomic nerve dysfunction, Parkinson's syndrome, cerebellar ataxia, and pyramidal sign. The clinical diagnosis and classification of MSA are mainly dependent on motion and non-motion symptoms, such as autonomic nerve dysfunction. In addition, an increasing amount of clinical and pathological evidence has shown that about half of the MSA patients exhibit distinct types and levels of cognitive dysfunction. However, cognitive dysfunction has not been included in the current diagnosis criteria of MSA. In most cases, it was even used as an exclusion criterion of MSA. Based on the neuroimaging, neuropathology and neuropsychology, this review summarized the morphological changes of the brain in the patients with MSA, and discussed possible brain regions that could be associated with cognitive impairment. The article may provide a theoretical basis for incorporating cognitive dysfunction into the criteria of MSA diagnosis.

THUR 101 SCA-1 with unusual early dysautonomia and delayed cerebellar signs

A 59-year-old right-handed bus driver presented with gradually worsening erectile dysfunction, urinary frequency and nocturia over 18 months. He had a past medical history of hypertension with regular medications including amlodipine, aspirin and atorvastatin. Initial examination revealed a mild bilateral intention tremor.The patient had undergone brain imaging showing brainstem and cerebellar atrophy with a ‘hot cross bun sign’. The patient was then referred for autonomic function tests that demonstrated mild cardiovascular autonomic changes, and suggested sympathetic dysfunction. A working diagnosis of multiple system atrophy (MSA) was made.Over the next two years, his tremor worsened with the development of slurred speech and unsteady gait. On examination, he had prominent fasciculations and wasting in the right shoulder, severe bilateral intention tremor with past-pointing. In addition he had Parkinsonism and signs of a sensorimotor neuropathy.This atypical clinical evolution with prominent neuropathy and cerebellar signs led to investigations for spinocerebellar ataxia (SCA), particularly type 2 or 3 (given the autonomic dysfunction). However, the genetic testing showed a mutation in ATXN1, confirming a diagnosis of SCA type 1.To our knowledge, this is the first reported case of prominent early autonomic dysfunction associated with SCA type 1.

Clinical and Imaging Features of Multiple System Atrophy: Challenges for an Early and Clinically Definitive Diagnosis.

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. Patients with MSA show various phenotypes during the course of their illness, including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. Patients with MSA sometimes present with isolated autonomic failure or motor symptoms/ signs. The median duration from onset to the concomitant appearance of motor and autonomic symptoms is approximately 2 years but can range up to 14 years. As the presence of both motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. In contrast, patients with MSA may show severe autonomic failure and die before the presentation of motor symptoms/signs, which are currently required for the diagnosis of MSA. Recent studies have also revealed that patients with MSA may show nonsupporting features of MSA such as dementia, hallucinations, and vertical gaze palsy. To establish early diagnostic criteria and clinically definitive categorization for the successful development of disease-modifying therapy or symptomatic interventions for MSA, research should focus on the isolated phase and atypical symptoms to develop specific clinical, imaging, and fluid biomarkers that satisfy the requirements for objectivity, for semi- or quantitative measurements, and for uncomplicated, worldwide availability. Several novel techniques, such as automated compartmentalization of the brain into multiple parcels for the quantification of gray and white matter volumes on an individual basis and the visualization of α-synuclein and other candidate serum and cerebrospinal fluid biomarkers, may be promising for the early and clinically definitive diagnosis of MSA.

Association study between multiple system atrophy and TREM2 p.R47H.

ObjectiveThe triggering receptor expressed on myeloid cells 2 (TREM2) p.R47H substitution (rs75932628) is a risk factor for Alzheimer disease (AD) but has not been well studied in relation to the risk of multiple system atrophy (MSA); the aim of this study was to evaluate the association between the TREM2 p.R47H variant and the risk of MSA.MethodsA total of 168 patients with pathologically confirmed MSA, 89 patients with clinically diagnosed MSA, and 1,695 controls were included. TREM2 p.R47H was genotyped and assessed for association with MSA. Positive results in the Taqman genotyping assay were confirmed by Sanger sequencing. The primary comparison involved patients with pathologically confirmed MSA and controls due to the definitive MSA diagnosis in the pathologically confirmed series.ResultsWe identified TREM2 p.R47H in 3 patients with pathologically confirmed MSA (1.79%), 1 patient with clinically diagnosed MSA (1.12%), and 7 controls (0.41%). Minimal AD pathology was observed for the pathologically confirmed MSA p.R47H carriers. For the primary comparison of patients with pathologically confirmed MSA and controls, risk of disease was significantly higher for p.R47H carriers (odds ratio [OR]: 4.39, p = 0.033). When supplementing the 168 pathologically confirmed patients with the 89 clinically diagnosed and examining the combined MSA series, the association with TREM2 p.R47H remained significant (OR: 3.81, p = 0.034).ConclusionsOur preliminary results suggest that the TREM2 p.R47H substitution may be a risk factor for MSA, implying a link to neuroinflammatory processes, especially microglial activation. Validation of this finding will be important, given our relatively small sample size; meta-analytic approaches will be needed to better define the role of this variant in MSA.

Prospective study of relevance of 123I-MIBG myocardial scintigraphy and clonidine GH test to distinguish Parkinson's disease and multiple system atrophy.

123I-MIBG myocardial scintigraphy and clonidine growth hormone test (CGH test) may help to distinguish multiple system atrophy (MSA) from Parkinson's disease (PD). Their relevance in the first-stage parkinsonism of uncertain etiology is unknown. Patients experiencing parkinsonism of ambiguous etiology were clinically classified into the PD group or the MSA group as initial clinical diagnosis (ICD). Then, CGH test and myocardial scintigraphy were performed. Clinical assessment was repeated throughout the disease course until the final clinical diagnosis (FCD) could be established according to the criteria of PD and MSA, respectively. Twenty-five patients with uncertain diagnosis were included (15 MSA and 10 PD as ICD). At the end of a 6-year follow-up, FCD was MSA in 11/25 patients and PD in 14/25. The CGH test and the scintigraphy showed a sensitivity of 82%, and a specificity of 71 and 93%, respectively, for the diagnosis of MSA. The combination of a normal scintigraphy (i.e., with myocardial MIBG uptake) with genitourinary dysfunction was the most relevant test to diagnose MSA, whereas an abnormal scintigraphy with a levodopa response of > 30% or an abnormal scintigraphy with the absence of OH was the most relevant combinations to diagnose PD. All these combinations had an accuracy superior than 90% and a specificity of 100%. Combinations of myocardial scintigraphy with genitourinary dysfunction, levodopa response of > 30%, or orthostatic hypotension could be of interest for the distinction between PD and MSA when the clinical diagnosis remains ambiguous at the first stage of the disease.

Multiple system atrophy and CAG repeat length: A genetic screening of polyglutamine disease genes in Italian patients

Multiple system atrophy (MSA) is an adult onset, progressive, neurodegenerative disorder of unknown etiology characterized by autonomic dysfunction, parkinsonism (MSA-P) and cerebellar ataxia (MSA-C). The phenotypic spectrum may present overlapping features with other neurodegenerative diseases, particularly the autosomal dominant inherited polyglutamine disorders.To investigate the possible contribution of CAG expansions in the MSA phenotype, we analyzed the triplet repeat length in the autosomal dominant causative genes for spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, 17, dentatorubral-pallidoluysian atrophy (DRPLA) and Huntington disease (HD) in a cohort of 246 Italian MSA patients. As comparison, 223 controls were also analyzed. The alleles were classified on the basis of CAG repeat length as “normal”, “intermediate” or “expanded” according to literature.The MSA patients (101 men/145 women) had a mean age at onset of 58 years and a mean age at genetic testing of 63 years. MSA-C patients had significantly younger age at onset and at examination in comparison to MSA-P (p < 0.0001). We identified a SCA1 intermediate allele in a MSA-C subject (36 CAG), a SCA2 intermediate allele in a MSA-P patient (31 CAG), and a pathologically expanded SCA2 allele (36 CAG) in a patient initially misdiagnosed as MSA-C.No intermediate or expanded SCA alleles were detected in controls. The distribution of CAG repeat length was similar among groups except for SCA1 gene that showed a higher percentage of longer normal alleles in MSA-C as compared to MSA-P and controls (p < 0.0001).This study supports the utility of polyQ genetic testing in the differential diagnosis of MSA, and may suggest a possible role of SCA1 repeat length as risk factor for MSA-C. SCA1 and SCA2 genetic screening is recommended in MSA Italian patients.

MRI Planimetry and Magnetic Resonance Parkinsonism Index in the Differential Diagnosis of Patients with Parkinsonism.

Differential diagnosis of multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration from Parkinson disease on clinical grounds is often difficult. MR imaging biomarkers could assist in a more accurate diagnosis. We examined the utility of MR imaging surface measurements (MR imaging planimetry) in the differential diagnosis of patients with parkinsonism. Fifty-two patients with Parkinson-plus (progressive supranuclear palsy, n = 24; corticobasal degeneration, n = 9; multiple system atrophy, n = 19), 18 patients with Parkinson disease, and 15 healthy controls were included. Corpus callosum, midbrain, and pons surfaces; relevant indices; and the Magnetic Resonance Parkinsonism Index were calculated. Corpus callosum subsection analysis was performed, and the corpus callosum posteroanterior gradient was introduced. A Magnetic Resonance Parkinsonism Index value of >12.6 discriminated progressive supranuclear palsy from other causes of parkinsonism with a 91% sensitivity and 95% specificity. No planimetry measurement could accurately discriminate those with multiple system atrophy with parkinsonism from patients with Parkinson disease. A corpus callosum posteroanterior gradient value of ≤191 was highly specific (97%) and moderately sensitive (75%) for the diagnosis of corticobasal degeneration versus all other groups. A midbrain-to-corpus callosum posteroanterior gradient ratio of ≤0.45 was highly indicative of progressive supranuclear palsy over corticobasal degeneration (sensitivity 86%, specificity 88%). MR imaging planimetry measurements are potent imaging markers of progressive supranuclear palsy and promising markers of corticobasal degeneration but do not seem to assist in the diagnosis of multiple system atrophy with parkinsonism.

The Case of Urosepsis Followed with the Diagnosis of Multiple System Atrophy in Intensive Care Unit

The Case of Urosepsis Followed with the Diagnosis of Multiple System Atrophy in Intensive Care Unit

The Bulbocavernosus Reflex in the Differential Diagnosis of Multiple System Atrophy with Predominant Parkinsonism and Parkinson's Disease.

Multiple system atrophy with predominant parkinsonism (MSA-P) is a degenerative disorder that presents with autonomic dysfunction, atypical parkinsonism, and ataxia. Parkinson’s disease (PD) is an age-related neurological disorder of the central nervous system. Differentiation between MSA-P and PD is important because treatments, complications, and prognoses differ. The bulbocavernosus reflex (BCR) tests the afferent and efferent signals of the pudendal nerve as well as the sacral cord. In this study, we investigated differences in BCR parameters between MSA-P and PD patients. Thirty-eight MSA-P patients and 32 PD patients were selected to participate in our electrophysiological investigations. The Keypoint EMG/EP system was used to induce the BCR, and latencies and amplitudes were recorded for systematic statistical analyses. Area under the curve of the receiver operating characteristic was used to assess the specificity and sensitivity of the BCR parameters. A BCR was elicited in 76.32% of MSA-P patients and 93.75% of PD patients. The BCR latencies of the MSA-P group were longer than those of the PD group (p < 0.001). In addition, the MSA-P group had a lower BCR amplitude compared to the PD and control groups (p < 0.001). We discovered the difference between MSA-P and PD through BCR latencies and amplitudes. Compared to PD patients, MSA-P patients have longer latencies and lower amplitudes. Therefore, the BCR may be used to discriminate between MSA-P and PD in some cases.

Serum microRNA expression profiling in patients with multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by α-synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR-16, which may induce the accumulation of α-synuclein. The target genes of some miRNAs upregulated in MSA (including miR-17, 20a, 24, 25, 30d and 451) were associated with autophagy-associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA.

Diagnosis of multiple system atrophy.

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.

Large postvoid residual is a strong predictor of the diagnosis of multiple system atrophy in patients with Parkinsonian syndrome

Background: It is difficult to differentiate multiple system atrophy (MSA) from Parkinson’s disease (PD) at least in the early stage. Urodynamic study (UDS) is useful in differentiating MSA from PD. However, many UDS parameters are difficult for neurologists to understand.

Proposal of modified autonomic failure criteria for the diagnosis of multiple system atrophy

Proposal of modified autonomic failure criteria for the diagnosis of multiple system atrophy

Postvoid residual predicts the diagnosis of multiple system atrophy in Parkinsonian syndrome

ObjectiveIt is difficult to differentiate multiple system atrophy (MSA) from Parkinson's disease (PD) at least in the early stage. Urodynamic study (UDS) is useful in differentiating MSA from PD. We aimed to clarify which UDS parameter was useful in differentiating MSA from PD. MethodsWe retrospectively reviewed 273 cases and performed UDS and external anal sphincter electromyography (EAS-EMG) in patients with MSA (n=182) and PD (n=91). We analyzed the utility of UDS parameters, including postvoid residuals (PVR), detrusor overactivity (DO), degree of bladder contraction, and mean duration of motor unit potentials (MUPs) in EAS-EMG, for differentiating MSA from PD. ResultsPVR>150ml during free-flow study strongly indicated MSA rather than PD (OR 8.723, 95% CI 2.612–29.130, p<0.001). ‘Weak detrusor’ also suggested MSA, but it was not a statistically significant indicator (OR 10.598, 95% CI 0.359–312.473, p=0.172). DO and neurogenic changes in EAS-EMG (mean duration of MUPs>10ms) did not significantly contribute to the differentiation of MSA from PD. ConclusionsPVR>150ml during free-flow study might be more useful than other UDS parameters in clinically differentiating MSA from PD.

Serum Lymphocyte-Associated Cytokine Concentrations Change More Rapidly over Time in Multiple System Atrophy Compared to Parkinson Disease

Objective: Chronic inflammatory processes contribute to the eventual death of motor neurons and the development of symptoms in both idiopathic Parkinson disease (PD) and multiple system atrophy (MSA). Given the faster rate of progression and more severe symptoms associated with MSA, we hypothesized that markers of inflammation would be more evident in the peripheral blood of MSA than PD patients, and that evidence of this inflammation might assist early diagnosis of MSA versus PD. Methods: We performed multiplex analysis to determine the concentrations of 37 immune-associated cytokines and chemokines isolated from the plasma of patients with PD (n = 25) and MSA (n = 14) and compared our results to those of age-matched controls (n = 15). We then applied a mixed-effect multiple regression model to determine if the concentration of cytokines in the plasma of patients with PD and MSA changed significantly over time. Results: Patients with MSA had a trend towards overall lower levels of immune-associated cytokines, while serum cytokine levels were increased in patients with PD. Statistically adjusted comparisons of overall changes in cytokine concentrations between the PD and MSA groups revealed higher concentrations of T-cell-associated cytokines TNFβ and IL-7 in PD. Comparison of samples taken over time revealed significantly faster rates of change in 4 different cytokine concentrations (IL-4, IL-15, IL-2, and IL-9) in patients with MSA versus patients with PD. Conclusions: Our results suggest that single measurements of plasma concentrations of inflammation-associated cytokines cannot be used to distinguish disease states. However, measurements made over time may correlate with pathogenesis. The significant changes in T-cell-associated cytokines may shed light on immune mechanisms that contribute to PD and MSA disease progression.