MSA-C Patients Research Articles

Differentiation of SCA2 from MSA‐C using proton magnetic resonance spectroscopic imaging

To assess and compare biochemical and volumetric features of the cerebellum in patients with spinocerebellar ataxia type 2 (SCA2) and patients with the cerebellar variant of multiple system atrophy (MSA-C). Nine genetically assigned SCA2 patients and six MSA-C patients who met the clinical criteria of MSA-C underwent a clinical and neuroradiological workup with respect to cerebellar features. The MR protocol consisted of a sagittal T1-weighted three-dimensional fast low-angle shot (3D FLASH) sequence and a transversal T2- and spin-density-weighted turbo spin-echo sequence. The proton magnetic resonance spectroscopic imaging ((1)H-MRSI) protocol consisted of two chemical shift imaging (CSI) sequences (echo time (TE) = 20 and 135 msec). Both short- and long-TE MR spectroscopy (MRS) images showed significant decreases in values for N-acetylaspartate to creatine (NAA/Cr), and choline to creatine (Cho/Cr) ratios in MSA-C and SCA2 compared to normal controls, though there was no difference between the two patient groups. In contrast, distinct cerebellar lactate (Lac) peaks were detected in seven SCA2 patients, and small peaks were detected in two. However, we did not detect any definite Lac peak in MSA-C or control subjects. MRSI revealed Lac pathology in SCA2 but not in MSA-C. Whether this indicates distinct pathogenetic mechanisms of cerebellar degeneration remains to be established.

MSA-C is the predominant clinical phenotype of MSA in Japan: Analysis of 142 patients with probable MSA

We investigated the clinical features and mode of disease progression in 142 patients with probable multiple system atrophy (MSA) according to the Consensus Criteria. The subjects included 84 men and 58 women with a mean age at onset of 58.2 ± 7.1 years (range: 38–79 years). Cerebellar signs were detected in 87.3% of these patients at the time of initial examination, and were found in 95.1% of them at latest follow-up. MSA-C was diagnosed in 83.8% of the patients at their first examination. Parkinsonism was initially detected in 28.9% of the patients, increasing to 51.4% at the latest follow-up. Among all of the subjects, only 16.2% were classified as having MSA-P on initial examination. At the latest follow-up, parkinsonian features had become predominant over cerebellar features in 24.6% of the 65 patients with MSA-C who were followed for more than 3 years. Although parkinsonism usually masked the signs of cerebellar involvement in MSA-C patients, none of the patients with MSA-P at an early stage showed predominance of cerebellar features at the latest follow-up. Parkinsonism is the predominant feature of MSA among Western patients, even at an early stage, but this study showed that cerebellar deficits are the main feature in Japanese patients. This difference of disease manifestations between ethnic groups suggests that genetic factors may influence the clinical phenotype of MSA.

Visualization and quantification of disease progression in multiple system atrophy

To visualize and quantify disease progression in multiple system atrophy (MSA) from cerebellar type (MSA-C), we combined two magnetic resonance imaging (MRI) techniques, voxel-based morphometry (VBM) and 3D-based volumetry. Patients suffering from MSA-C (n = 14) were imaged twice with an interval of 2.0 +/- 0.2 years. We first applied VBM to map brain morphology changes between MSA patients and controls and to identify brain areas that showed a significant amount of atrophy. Using 3D-based volumetry, we confirmed that in MSA-C patients, the brainstem including medulla and pons, vermis and cerebellar hemispheres, caudate nucleus and putamen showed significant atrophy compared with controls. Next, we used 3D-based volumetry to analyze the atrophy rates. Atrophy rates in patients with MSA were significantly different from controls for putamen (-11.4% +/- 2.6%/year), vermis (-12.3% +/- 2.9%/year), and cerebellar hemispheres (-6.6% +/- 1.1%/year). The results show that 3D-based MRI volumetry is a tool that allows the disease progression of MSA to be followed over a time period of 2 years and suggest that it may serve as a surrogate marker in clinical trials to measure disease progression.

Cortical atrophy in the cerebellar variant of multiple system atrophy: A voxel‐based morphometry study

This study aimed to determine in vivo the atrophy patterns in clinically established cerebellar variant of multiple-system atrophy (MSA-C) using voxel-based morphometry (VBM). Thirteen patients with MSA-C (12 probable, 1 possible) and 13 healthy controls matched for age and sex were included. High-resolution MR images were acquired with a 1.5 T scanner. Images were normalized onto a study-specific template, segmented into the tissue compartments, modulated with the Jacobian determinants, and finally smoothed with a Gaussian kernel filter of 10 mm. The general linear model was used to assess statistical differences in gray and white matter. Infratentorial atrophy was observed in the cerebellar hemispheres, vermis, mesencephalon, and pons of MSA-C patients. Supratentorial volume loss was found in orbitofrontal and mid-frontal regions as well as in temporomesial and insular areas of both hemispheres. A negative correlation was observed between a cerebellar ataxia score and the volume of cerebellar hemispheres, peduncles, and pons. To compare this atrophy pattern to that of spinocerebellar ataxia (SCA2), which was previously reported by our group, a conjunction analysis was assessed. We observed a volume loss shared by both disorders comprising the cerebellum, vermis, pons, mesencephalon, orbitofrontal, mid-frontal, and temporomesial cortex of both hemispheres as well as the left insular cortex.

Clinical Characteristics of Patients with Multiple System Atrophy in Singapore

Introduction: Our study aimed to describe the clinical features of multiple system atrophy (MSA) in Singapore and verify its diagnosis using the consensus statement in the diagnosis of MSA. Materials and Methods: All patients suspected to have MSA between 1995 and March 2005 were identified from the Movement Disorders database and the autonomic function testing results. The medical records were reviewed using a standardised data collection form. The diagnosis of MSA was verified using the consensus statement. Disease progression was evaluated using 2 pre-determined events: aid-requiring walking and wheelchair use. Results: Seventy-two per cent (33/46) fulfilled the consensus statement. There were 85% Chinese, 9% Malays, and 6% Indians. The mean age at onset of the disease was 60 ± 10 years. We found a predominance of males (M:F = 1.5:1) as well as MSA-C cases (67%). The most common initial presenting features were parkinsonism and cerebellar signs (27% each). Abnormal neuroimaging was seen in 29 patients (91%). Autonomic function testing was abnormal in 58% (7/12). The risk for aid-requiring walking and wheelchair use at 3 years from onset of the disease was 31% and 17%, respectively. By 5 years, this had increased to 45% and 30%, respectively. There was no difference in the events rate between MSA subtypes. Conclusions: The clinical characteristics of MSA in Singapore are presented. Our study revealed a predominance of MSA-C patients as well as a later age at onset of disease and longer median time to aid-requiring walking and wheelchair use compared to Japanese patients.

Swallowing function in patients with multiple-system atrophy with a clinical predominance of cerebellar symptoms (MSA-C)

We investigated the swallowing function of 21 patients with multiple system atrophy with a clinical predominance of cerebellar symptoms (MSA-C) by videofluoroscopy (VF). Twenty-six VF examinations were performed at various time points, and they were divided into three groups according to the duration following disease onset: Group A had 1 to 3 years following disease onset (the early stage of the disease), group B had 4 to 6 years following disease onset (the middle stage of the disease), and group C had more than 7 years following disease onset (the late stage of the disease). Swallowing function in the oral phase became gradually disturbed over the progression of MSA. Delayed bolus transport from the oral cavity to the pharynx was already seen in 50% of the patients in group A, and it was seen in more than 85% of the patients in group C. Bolus holding in the oral cavity was slightly disturbed in group A, but it was seen in 57% of the patients in group C. Our study shows that parkinsonism is related to swallowing dysfunction in MSA, but cerebellar dysfunction also affects coordination of the tongue; bolus transport in the oral cavity was disturbed in the early stage of disease. Progression of cerebellar dysfunction and overlapped parkinsonism will worsen tongue movement, and in the late stage of the disease, swallowing function of the oral phase (bolus transport and bolus holding) was remarkably disturbed. Swallowing function in the pharyngeal phase was not significantly correlated to the duration of the disease; however, our study showed that swallowing function in the pharyngeal phase was not assessed fully by VF examination in MSA-C only. Combination with other examinations, such as manometry and electromyography, may be useful, especially in the late stage of the disease. In addition, an analysis concerning the relationship between aspiration seen on VF examination and a history of aspiration pneumonia in MSA-C patients suggested that the sensory system at the larynx and trachea should also be assessed in patients in the late stage of MSA-C.

Myoclonic tremulous movements in multiple system atrophy are a form of cortical myoclonus

We prospectively studied the clinical and electrophysiological features of myoclonic tremulous movements in patients with multiple system atrophy (MSA). Among 42 consecutive patients, 12 MSA-p (parkinsonian type) and 3 MSA-c (cerebellar type) patients showed small-amplitude myoclonic movements. These movements occurred in the distal part of the arms and fingers, particularly in posture or during voluntary movements. We conducted detailed electrophysiological studies in 11 patients. Electromyographic recordings showed irregular bursts of brief duration often synchronously involving the antagonistic muscles. Somatosensory evoked responses were slightly enlarged in some patients. Long-latency reflexes were enhanced in 7 patients. A jerk-locked averaging technique revealed premyoclonic cortical potentials in 9 patients. These findings suggest that small-amplitude myoclonic movements in MSA are a form of cortical myoclonus.

Olfactory dysfunction in cerebellar ataxia and multiple system atrophy.

Olfactory dysfunction has been reported in Parkinson's (PD) and Alzheimer's disease (AD). We studied olfactory function in eight patients with multiple system atrophy of cerebellar type (MSA-C), eleven patients with sporadic cerebellar ataxia of unknown etiology and thirteen controls matched for age and gender. Subjects received tests for n-butanol odor thresholds, odor identification, and odor discrimination. Olfactory thresholds were abnormally high in 16% of the patients. Odor discrimination and odor identification were impaired in 44 % and 74% of the patients, respectively. There was no significant difference in olfactory function between patients with sporadic ataxia of unknown etiology and MSA-C patients. The present data suggest that olfactory dysfunction is common to various neurodegenerative disorders and not specifically restricted to PD or AD. Cerebellar dysfunction affected suprathreshold olfactory function more severely than odor thresholds. Thus cerebellar lesions may affect the processing of odor-related information to a higher degree than the transport of odorants to the receptor through sniffing.

MRI-based volumetric differentiation of sporadic cerebellar ataxia

The term idiopathic cerebellar ataxia (IDCA) designates a variety of cerebellar syndromes that may present with a purely cerebellar syndrome (IDCA-C) or with additional extracerebellar features (IDCA-P). Multiple system atrophy is also a sporadic neurodegenerative disorder of unknown origin that may cause prominent cerebellar symptoms (MSA-C). The final neuropathological answer to the question whether IDCA-P and MSA-C represent different varieties of one disease or two distinct entities is still lacking. Three-dimensional MRI-based volumetry allows morphological investigations intra vitam. Volumetric analysis of cerebellum, brainstem and basal ganglia was therefore performed in 46 patients with sporadic cerebellar ataxia and 16 age-matched healthy controls. Patients with dementia were excluded from the study since cognitive impairment is an exclusion criterion for the diagnosis of MSA. Cerebellar patients were clinically divided into two groups: 33 patients with multiple system atrophy with prominent cerebellar symptoms (MSA-C) and 13 patients with extracerebellar features not corresponding to MSA-C (IDCA-P). There was evidence for substantial cerebellar atrophy in both cerebellar groups while additional brainstem atrophy was significantly more pronounced in MSA-C patients. Absolute caudate and putamen atrophy was found to be restricted to single MSA-C individuals while group comparisons of mean volumes did not yield significant differences from controls. Based on the volumetric data, diagnosis could be correctly predicted in 94% of control, 82% of MSA-C and 100% of IDCA-P individuals. The finding of specific imaging characteristics strengthens (i) the value of MRI volumetry in separating MSA-C from other types of sporadic cerebellar ataxia, and (ii) the hypothesis of two independent neurodegenerative disorders in MSA-C and IDCA-P.

Exaggerated auditory startle responses in multiple system atrophy: a comparative study of parkinson and cerebellar subtypes

Auditory startle responses (ASRs) have recently been reported to be exaggerated in cranial and peripheral nerve supplied muscles of patients with multiple system atrophy (MSA). ASRs displayed increased probability, amplitude and duration, shorter onset latency, and reduced habituation in comparison with healthy subjects. In order to investigate whether certain ASR features may differentiate MSA subtypes, the authors studied ASRs in 21 MSA patients (olivopontocerebellar type, MSA-C: n = 8, striatonigral type, MSA-P: n = 13), and 17 age-matched normal controls. ASRs were elicited by binaural high-intensity auditory stimuli which differed randomly in tonal frequency and intensity (250 Hz, 90 db; 500 Hz, 105 db; 750 Hz, 105 db; 1000 Hz, 110 db normal hearing level), presented through tubal insert phones. Reflex electromyographic activity was simultaneously recorded with surface electrodes from masseter, orbicularis oculi, sternocleidomastoid, biceps brachii, abductor pollicis brevis, rectus femoris, tibialis anterior, and soleus muscles. Eighteen MSA patients (86%) had exaggerated ASRs as compared to normal subjects. At group level, indices of ASR disinhibition including increased ASR probability (in extremity muscles), shortened onset latency, and enlarged response magnitude were significantly more marked in MSA-P as compared to MSA-C patients. ASR probability showed habituation in normal subjects, less in MSA-P. and none in MSA-C patients. Three MSA-patients had no ASRs except in orbicularis oculi muscle. Although absent ASRs may occur in some MSA patients, most of them exhibit exaggerated ASRs. This finding may reflect disinhibition of lower brainstem nuclei due to the degenerative disorder. ASRs were significantly more disinhibited in MSA-P versus MSA-C. suggesting involvement of different neural structures in the two MSA-subtypes.

Freezing of gait in multiple system atrophy (MSA)

Background. Freezing of gait (FOG) is a mysterious symptom, observed in different parkinsonian syndromes, but considered to be rare in multiple system atrophy (MSA). Objective. To assess the frequency of FOG in patients with MSA. Method. We studied the presence of FOG in 28 patients with clinical diagnosis of MSA. 21 patients had probable MSA and 7 had possible MSA. The clinical diagnosis was based on neurological examination performed by at least two experienced movement disorders specialists as well as on the results of ancillary examinations and the course of the disease. In 22 patients MSA was predominated by parkinsonism (MSA-P) and in 6 by cerebellar signs (MSA-C). The patients' mean age was 66.8±10.3 years, mean disease duration 6.4±4.0 years and mean worst Hoehn and Yahr (H&Y) stage was 3.6±0.6. Presence and severity of FOG was assessed during the last office visit, by the recently validated FOG questionnaire (FOG-Q), with a maximal score of 24, while patients that received at least one point in the last four questions were classified as having FOG. Severity of FOG was determined by the sum of these last four out of six questions (maximal score is 16). FOG-Q total score reflected general function and walking ability disturbances, caused by FOG. The comparison between groups of patients was performed by way of the Mann–Whitney two-sample test and chi-square or Fisher's exact tests. Correlations between various parameters were calculated using Spearman's correlation coefficient. Results. Twenty-one patients were able to walk and 7 were bedridden at the time of the study. FOG appeared in a total of 75% of all MSA patients (in 82% of patients with MSA-P and in 50% patients with MSA-C). In the MSA-P group disease duration was about the same among ‘freezers’ and ‘non-freezers’, while among the MSA-C patients it was significantly shorter in the non-freezers. Mean score of the freezing subdivision of the FOG-Q was 8.2±5.1 for MSA-P group and 4.5±5.1 for MSA-C one. Mean FOG-Q total score was 9.1±4.0 and 6.2±4.6 ( p>0.05) for MSA-P and MSA-C patients, respectively. Conclusion. Freezing of gait is a common symptom in MSA, both in MSA-P and MSA-C.

Application of the International Cooperative Ataxia Scale rating in multiple system atrophy.

We assessed the International Cooperative Ataxia Scale (ICARS) as a means of extracting and rating cerebellar signs in multiple system atrophy (MSA). Cross-sectional analysis of internal consistency, factor structure, and correlation with parkinsonism severity (Unified Parkinson's Disease Rating Scale [UPDRS] III) of the ICARS, in 50 unselected MSA patients (mean age, 67.6 years; mean disease duration, 5.5 years), 50 age-matched and disease duration-matched Parkinson' disease (PD) patients, and 50 control subjects. Fifteen patients (30%) had MSA-C (cerebellar subtype) and 35 (70%) MSA-P (parkinsonism subtype), and 66% had at least one cerebellar sign. The total ICARS score was much higher (fivefold) in MSA compared to PD patients. The ICARS score was twofold higher in MSA-C than in MSA-P patients. MSA-C patients had a higher score than MSA-P mainly on posture and gait disturbances and kinetic functions subscores. All the ICARS items were significantly more severe in MSA than in PD patients, who in turn scored higher than the controls. In MSA, internal consistency was excellent (Cronbach = 0.93). Factor structure analysis revealed four clinically distinct subscores, in accordance with the scale structure, which accounted for 70% of the variance. The ICARS showed less consistency and accuracy in PD patients; however, the ICARS scores significantly correlated with the UPDRS-III scores in both MSA and PD patients. The ICARS appears a useful tool to extract and rate the severity of cerebellar signs in MSA; however, it is clearly contaminated by parkinsonian features.

Impaired chemosensitivity to hypoxia is a marker of multiple system atrophy.

Sudden death is common in patients with multiple system atrophy (MSA). In its early stages, the cerebellar presentation MSA-C can be indistinguishable from idiopathic late-onset cerebellar ataxia. We studied the hypoxic ventilatory response in MSA-C and idiopathic late-onset cerebellar ataxia patients. Six patients with idiopathic late-onset cerebellar ataxia that later evolved to MSA had impaired hypoxic ventilatory response when minimal autonomic failure was still present, whereas for patients with unimpaired hypoxic ventilatory response their diagnosis remained idiopathic late-onset cerebellar ataxia. The demonstration of impaired hypoxic ventilatory response appears to be a good marker enabling earlier diagnosis of MSA in patients presenting with idiopathic late-onset cerebellar ataxia.