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PubMed1992

Altered vasopressin response to metoclopramide in multiple system atrophy: evidence of a cholinergic defect in the hypothalamus.

Multiple system atrophy (MSA) is a heterogeneous group of central neurological degenerations often associated with diffuse deterioration of the hypothalamic cholinergic neurons. In the hypothesis of an altered cholinergic regulation of vasopressin release, we evaluated vasopressin response to metoclopramide (20 mg i.v.), a cholinomimetic agonist, in 12 MSA patients. In the same patients the hemodynamic and osmolal control of vasopressin was also evaluated. We found that MSA patients had significantly lower basal plasma vasopressin values and higher plasma osmolality than control subjects. However, they displayed a normal vasopressin response to osmotic stimulation. During head-up tilting, orthostatic hypotension occurred in all patients, and the vasopressin response to hypotension was severely blunted in 5 of 12 patients, thus demonstrating the presence of a lesion of the afferent noradrenergic pathways. Metoclopramide increased vasopressin in control subjects, whereas MSA patients did not display any increase in vasopressin. These results clearly indicate that cholinergic neurons that regulate vasopressin release are damaged in MSA. Such an alteration may be dissociated from the lesion of the afferent noradrenergic pathways. As a consequence of the altered vasopressin release, MSA patients show lower plasma vasopressin levels with consequent propensity to dehydration and hypovolemia, which may further aggravate their hypotension.

Autonomic Nervous System Diseases↗

PubMed2004

Abnormal baroreceptor-mediated vasopressin release as possible marker in early diagnosis of multiple system atrophy.

BACKGROUND: Although autonomic failure (AF) is a critical symptom of multiple system atrophy (MSA), it may not appear until late in the disease process. OBJECTIVES: To clarify whether a detailed investigation of the autonomic nervous system in patients with MSA without overt AF demonstrates latent lesions of central cardiovascular control circuits and facilitates the early diagnosis of MSA. METHODS: Autonomic function tests, and plasma noradrenaline (NA) and vasopressin (AVP) responses to head-up tilt (HUT), were studied in 12 patients with MSA with AF (probable MSA), 12 with MSA without overt AF (possible MSA), and 24 controls. RESULTS: Abnormalities of cardiovascular autonomic function tests were prominent in the first group but mild in the second. Plasma NA and AVP increments upon HUT differed significantly among all three groups. CONCLUSIONS: These results indicate that probable MSA involves diffuse degeneration of central cardiovascular control circuits. On the other hand, the discrepancies in possible MSA suggest a vulnerability of the noradrenergic (A1) neurones of the caudal ventrolateral medulla that are involved in AVP secretion. This finding also suggests that AVP increment may be useful as a diagnostic tool in the early stages of MSA.

Aged↗

PubMed1994

Infantile multiple system atrophy with cytoplasmic and intranuclear glioneuronal inclusions.

This report presents a case of infantile multiple system atrophy with probably autosomal recessive inheritance. The female patient developed generalized muscular hypotonia, myoclonias and tonic-clonic seizures at the age of 8 months, followed by gradual development of choreoathetotic hyperkinesia and increasing psychomotor retardation. Metabolic disease was ruled out and the child died of aspiration pneumonia at the age of 5 years. General autopsy was unremarkable, but neuropathological examination showed degeneration of cerebellum, inferior olives, medial thalamus, Clarke's nucleus, anterior horn cells, corticospinal, spinocerebellar tracts, and posterior columns. Immunohistochemically many neurons contained intranuclear and intracytoplasmic ubiquitin-positive inclusions, which did not contain neurofilament or tau epitopes and ultra-structurally consisted of granulofilamentous material. We tentatively classify this case as a form of infantile multiple system atrophy linked to neuronal intranuclear hyaline inclusion disease.

Cell Nucleus↗

PubMed2007

Pyramidal tract degeneration in multiple system atrophy: the relevance of magnetization transfer imaging.

The clinical features of multiple system atrophy (MSA) include four domains: autonomic failure/urinary dysfunction, Parkinsonism, cerebellar ataxia, and corticospinal tract dysfunction. Although the diagnosis of definite MSA requires pathological confirmation, magnetic resonance imaging (MRI) studies have been shown to contribute to the diagnosis of MSA. Although pyramidal tract dysfunction is frequent in MSA patients, signs of pyramidal tract involvement are controversially demonstrated by MRI. We evaluated the pyramidal involvement in 10 patients (7 women) with clinically probable MSA, detecting the presence of spasticity, hyperreflexia, and Babinski sign, as well as demonstrating degeneration of the pyramidal tract and primary motor cortex by MRI in all of them. Our article also discusses key radiological features of this syndrome. In MSA, pyramidal tract involvement seems to be more frequent than previously thought, and the clinicoradiological correlation between pyramidal tract dysfunction and degeneration may contribute to the understanding of the clinical hallmarks of MSA. MRI may also add information regarding the differential diagnosis of this syndrome.

Female↗

PubMed2002

Do published criteria improve clinical diagnostic accuracy in multiple system atrophy?

OBJECTIVE: To assess the accuracy of a clinical diagnosis of multiple system atrophy (MSA) and compare it to the Quinn and Consensus criteria for MSA using neuropathologically examined cases from the Queen Square Brain Bank for Neurological Disorders. METHODS: Fifty-nine cases with a neurologic diagnosis of MSA when last assessed prior to death were studied. RESULTS: In 51 (86%) of these cases, the diagnosis of MSA was confirmed pathologically. False positive diagnoses included PD (n = 6), progressive supranuclear palsy (n = 1), and cerebrovascular disease (n = 1). When applying either set of diagnostic criteria, a diagnosis of probable MSA gave lower sensitivity but higher positive predictive value than one of possible MSA. Application of either set of diagnostic criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by the last clinic visit. CONCLUSIONS: This study shows a high diagnostic accuracy for the clinical diagnosis of MSA by neurologists, with PD accounting for most of the false positive diagnoses. Application of either Quinn or Consensus criteria was superior to actual clinical diagnosis made early in the disease, but there was little difference by last clinic visit.

Adult↗

PubMed2006

Effect of object transport on grasp coordination in multiple system atrophy.

We examined the effects of the parkinsonian variant of multiple-system atrophy (MSA-P) on grasp and forward transport and release of an object. Twelve patients with MSA-P and 10 age-matched control subjects performed the task with each of three object weights (200, 400, 800 gm). Subjects moved at a self-selected pace using a precision grip. The grip (normal) and load (tangential) forces and the object position were recorded. Results indicate subjects with MSA-P have temporal and force coordination deficits. Temporal delays were seen in all subjects with MSA-P, leading to prolonged overall movement times compared to control subjects. These delays occurred throughout the task, with significantly longer transport phases and delays releasing the object. Despite demonstrating an appropriate anticipatory scaling of forces, with increasing grip and load forces for heavier weights, force coordination was compromised in subjects with MSA-P. These subjects generated significant negative load forces prior to transporting the object. In addition, during the transport phase, subjects with MSA-P generated highly variable grip forces. Overall, the results indicate that subjects with MSA-P demonstrate bradykinesia and difficulty coordinating components of an object transport task.

Aged↗

PubMed2006

Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG).

The disease-specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinson's disease staging, Schwab England Activities of Daily Living (SE ADL), and a three-point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA-parkinsonian, 58%; MSA-cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P<0.0001) and UMSARS I scores by 35.6% (P<0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Adult↗

PubMed1997

Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration.

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown cause. The only case-control study conducted in MSA patients to date suggested a possible contributory genetic component in the pathogenesis of this disorder. The aim of this study was to evaluate a possible overlap between clinically or pathologically well-defined MSA and other conditions with an identified genetic defect causing spinocerebellar degeneration in humans or mutant mice strains. The spinocerebellar ataxia type 1 and 3 genes (SCA1 and SCA3) were analyzed for a pathologic expansion in 80 patients with MSA to evaluate a possible overlap between MSA and SCA1 or SCA3. Weaver mice and lurcher mice are animal models for spinocerebellar degeneration; both share pathologic features with MSA. We sequenced the H5 pore region of the human homologue of the weaver mouse gene, hiGIRK2, in all our patients. In lurcher mice, previous biochemical studies have shown a decreased intracellular response to insulin-like growth factor 1 (IGF-1) in the cerebellar cortex, and we thus investigated the possibility of an allelic association between MSA and the receptor for IGF-1. In addition, we evaluated a possible involvement of the ciliary neurotrophic factor gene (CNTF) and examined the role of HLA-A32 to clarify the conflicting data from previous studies. No changes were detected in any of the analyzed genes. Our studies strongly suggest that MSA is an autonomous syndrome distinct from identified genetic causes for spinocerebellar degeneration.

Alleles↗

PubMed2002

Dystonia in multiple system atrophy.

OBJECTIVE: To delineate the frequency and nature of dystonia in multiple system atrophy (MSA). METHODS: A cohort of 24 patients with clinically probable MSA over the past 10 years were prospectively followed up. Motor features were either dominated by parkinsonism (MSA-P subtype, n=18) or cerebellar ataxia (MSA-C, n=6). Classification of dystonic features and their changes with time was based on clinical observation during 6-12 monthly follow up visits. Parkinsonian features and complications of drug therapy were assessed. Most patients (22/24) died during the observation period. Neuropathological examination was confirmatory in all of the five necropsied patients. RESULTS: At first neurological visit dystonia was present in 11 (46%) patients all of whom had been levodopa naive at this time point. Six patients (25%) exhibited cervical dystonia (antecollis) (MSA-P n=4, MSA-C n=2), five patients (21%) showed unilateral limb dystonia (MSA-P n=4; MSA-C n=1). A definite initial response to levodopa treatment was seen in 15/18 patients with MSA-P, but in none of the six patients with MSA-C. A subgroup of 12 patients with MSA-P developed levodopa induced dyskinesias 2.3 years (range 0.5-4) after initiation of levodopa therapy. Most patients had peak dose craniocervical dystonia; however, some patients experienced limb or generalised dystonia. Isolated peak dose limb chorea occurred in only one patient. CONCLUSION: The prospective clinical study suggests that dystonia is common in untreated MSA-P. This finding may reflect younger age at disease onset and putaminal pathology in MSA-P. Levodopa induced dyskinesias were almost exclusively dystonic affecting predominantly craniocervical musculature. Future studies are required to elucidate the underlying pathophysiology of dystonia in MSA.

Aged↗

PubMed1990

Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

Using positron emission tomography (PET), we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, but while function in the posterior part of the putamen was severely impaired (45% of normal), function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD, being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2000

Depression in multiple system atrophy: a case report.

A 53-year-old woman who developed depression as the first symptom of multiple system atrophy was treated. Depression was followed successively by autonomic failure, parkinsonism and cerebellar ataxia. Treatment with L-DOPA, L-threo-DOPS, and thyroid releasing hormone was associated with improvement of autonomic failure and parkinsonism. As for depression, scores on the Zung scale and the Hamilton scale improved from 58 to 49 and from 30 to 22, respectively, This case is remarkable in that depression preceded neurologic dysfunction and was managed successfully by antiparkinsonian medication. A common underlying disturbance may be responsible for the depression and neurologic dysfunction in multiple system atrophy.

Antidepressive Agents↗

PubMed2005

Camptocormia or Pisa syndrome in multiple system atrophy.

Although a mild stooped posture is a hallmark of parkinsonism, extreme trunk forward flexion is not common. This phenomenon was described in different etiological entities and called camptocormia. Other similar presentations called Pisa syndrome and antecollis were described mainly in extrapyramidal disorders. Authors present two cases of probable multiple system atrophy (MSA) with predominant parkinsonism and Pisa syndrome (or camptocormia). Both of them were previously misdiagnosed as idiopathic Parkinson's disease (PD) and one was reported 1 year earlier. The typical clinical presentation fulfilling the diagnostic criteria for multiple system atrophy, rapid progression with lack of responsiveness to L-DOPA and apomorphine and typical MRI putaminal pathology observed in both cases allowed us to make a diagnosis. Accuracy of clinical diagnosis in multiple system atrophy is still very poor. Therefore, unusual or rare clinical presentations may support the final diagnosis. The camptocormia, Pisa syndrome and antecollis may represent the continuum of the same motor phenomenon and most of the authors refer them to unusual form of axial dystonia. According to many clinical presentations on different forms of camptocormia/Pisa syndrome authors conclude that not etiology, but the localization of specific lesion, probably within putamen is responsible for that form of dystonia. In cases of parkinsonism and severe forward flexion of trunk multiple system atrophy, diagnosis should be considered.

Diagnosis, Differential↗

PubMed1997

Contrast detection, discrimination and adaptation in patients with Parkinson's disease and multiple system atrophy.

Visual spatial contrast thresholds and suprathreshold contrast matches were measured before and after adaptation to high-contrast sinewave gratings in patients with Parkinson's disease (n = 27), patients with multiple system atrophy (n = 6) and a group of age-matched control patients without CNS disease (n = 27). Contrast thresholds were higher in the Parkinson's disease patients than in either the multiple system atrophy patients or control patients. The effect of contrast adaptation on both contrast thresholds and matches was approximately equal in the three groups. This suggests that contrast adaptation is not affected by these CNS disorders and is consistent with the hypothesis that the loss in contrast sensitivity in Parkinson's disease is mediated by retinal effects. The results are discussed in terms of the underlying pathology of the visual deficits in Parkinson's disease and the possible diagnostic implications for differentiating Parkinson's disease and multiple system atrophy.

Adaptation, Ocular↗

PubMed2006

Respiratory insufficiency as the primary presenting symptom of multiple-system atrophy.

BACKGROUND: Respiratory stridor, sleep-disordered breathing, and respiratory insufficiency are part of the clinical spectrum of multiple-system atrophy (MSA). We have encountered cases where these were presenting symptoms, with the diagnosis of MSA being initially unrecognized. OBJECTIVE: To describe cases in which breathing difficulties were the initial and primary manifestation of MSA. DESIGN: Database review from January 1, 1996, through October 31, 2005. SETTING: Mayo Clinic, Rochester, Minn. PATIENTS: All patients diagnosed as having MSA, cross-referenced for apnea, hypopnea, or hypoventilation. On review, we included only cases in which respiratory dysfunction was the primary initial clinical event in MSA, excluding equivocal cases. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Characteristics and clinical course of patients. RESULTS: Six cases were identified in which substantial respiratory insufficiency occurred as an early, presenting symptom of MSA. Three patients had been examined emergently for acute respiratory distress before the ultimate diagnosis of MSA; the other 3 patients were diagnosed as having obstructive sleep apnea unresponsive to therapy, with bilateral vocal cord paralysis found on ear, nose, and throat examination. Stridor was noted early in the course in all. All patients required tracheostomy, and all eventually developed features consistent with probable MSA. CONCLUSIONS: Multiple-system atrophy may occasionally present as primary respiratory failure or dysfunction, with initially mild motor and autonomic symptoms. Otherwise unexplained central respiratory failure, bilateral vocal cord paralysis, stridor, or refractory central sleep apnea should prompt consideration of MSA.

Aged↗

PubMed2002

Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

We investigated the disease progression and survival in 230 Japanese patients with multiple system atrophy (MSA; 131 men, 99 women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years). Cerebellar dysfunction (multiple system atrophy-cerebellar; MSA-C) predominated in 155 patients, and parkinsonism (multiple system atrophy-parkinsonian; MSA-P) in 75. The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic involvement within 3 years of onset had a significantly increased risk of not only developing advanced disease stage but also shorter survival (P < 0.01). MSA-P patients had more rapid functional deterioration than MSA-C patients (aid-requiring walking, P = 0.03; confinement to a wheelchair, P < 0.01; bedridden state, P < 0.01), but showed similar survival. Onset in older individuals showed increased risk of confinement to a wheelchair (P < 0.05), bedridden state (P = 0.03) and death (P < 0.01). Patients initially complaining of motor symptoms had accelerated risk of aid-requiring walking (P < 0.01) and confinement to a wheelchair (P < 0.01) compared with those initially complaining of autonomic symptoms, while the time until confinement to a bedridden state and survival were no worse. Gender was not associated with differences in worsening of function or survival. On MRI, a hyperintense rim at the lateral edge of the dorsolateral putamen was seen in 34.5% of cases, and a 'hot cross bun' sign in the pontine basis (PB) in 63.3%. These putaminal and pontine abnormalities became more prominent as MSA-P and MSA-C features advanced. The atrophy of the cerebellar vermis and PB showed a significant correlation particularly with the interval following the appearance of cerebellar symptoms in MSA-C (r = 0.71, P < 0.01, r = 0.76 and P < 0.01, respectively), but the relationship between atrophy and functional status was highly variable among the individuals, suggesting that other factors influenced the functional deterioration. Atrophy of the corpus callosum was seen in a subpopulation of MSA, suggesting hemispheric involvement in a subgroup of MSA patients. The present study suggested that many factors are involved in the progression of MSA but, most importantly, the interval from initial symptom to combined motor and autonomic dysfunction can predict functional deterioration and survival in MSA.

Activities of Daily Living↗

PubMed1988

Low leukocyte glutamate dehydrogenase activity does not correlate with a particular type of multiple system atrophy.

Leucocyte glutamate dehydrogenase (GDH) activity was measured in 26 normal control subjects, 20 patients with multiple system atrophy presenting features of either olivopontocerebellar atrophy or striatonigral degeneration and in a heterogenous group of 15 patients with spinocerebellar degenerations. A broad range of GDH activity was found in all three groups. Low activity failed to correlate with a specific clinical entity. Patients followed to post-mortem examination to date have demonstrated histological features of at least three distinct morbid entities. It is concluded, contrary to earlier reports including the authors', that low leukocyte GDH activity does not identify a particular type of multiple system atrophy.

Adult↗

PubMed2002

Diffusion-weighted MRI differentiates the Parkinson variant of multiple system atrophy from PD.

OBJECTIVE AND BACKGROUND: Routine MRI as well as MR volumetry and MRS have been shown to contribute to the differential diagnosis of the Parkinson variant of multiple system atrophy (MSA-P) and PD. However, it is currently unknown whether diffusion-weighted imaging (DWI) discriminates these disorders. METHODS: Ten patients with MSA-P (mean age, 64 years) were studied, 11 with PD (mean age, 64 years), and seven healthy volunteers (mean age, 59 years) matched for age and disease duration. Regional apparent diffusion coefficients (rADC) were determined in different brain regions including basal ganglia, gray matter, white matter, substantia nigra, and pons. RESULTS: Patients with MSA-P had higher putaminal rADC (median 0.791 x 10(3)/mm(2)/s) than both patients with PD (median 0.698 x 10(3)/mm(2)/s, p < 0.001) and healthy volunteers (median 0.727 x 10(3)/mm(2)/s, p < 0.001). There were no significant differences in putaminal rADC between patients with PD and healthy volunteers. Moreover, none of the putaminal rADC values in the PD and control group surpassed the lowest value in the MSA-P group. There were no significant group differences in the rADC values in other brain regions such as pons, substantia nigra, globus pallidus, caudate nucleus, thalamus, or gray and white matter. Putaminal rADC values correlated significantly with Unified PD Rating Scale OFF scores in patients with MSA as measured by the Spearman rank test. CONCLUSION: DWI, even if measured in the slice direction only, is able to discriminate MSA-P and both patients with PD and healthy volunteers on the basis of putaminal rADC values. The increased putaminal rADC values in Parkinson variant of multiple system atrophy are likely to reflect ongoing striatal degeneration, whereas most neuropathologic studies reveal intact striatum in PD. Diffusion-weighted imaging may represent a useful diagnostic tool that can provide additional support for a diagnosis of Parkinson variant of multiple system atrophy.

Aged↗

PubMed1999

[Prognosis of multiple system atrophy--survival time with or without tracheostomy].

Prognosis of 21 patients with multiple system atrophy (MSA) who deceased or received tracheostomy is described. The percentage of patients with MSA among the cases of spinocerebellar degeneration was 40% in National Tokyo Hospital. There were 12 women and 9 men, and the mean age at onset was 56 years. Seventy-four percent of MSA patients was olivopontocerebellar atrophy (OPCA), 22% was striatonigral degeneration (SND). The mean age of 17 deceased patients (10 women, and 7 men) was 65.5 years. Ten patients did not undergo tracheostomy and deceased, and 11 patients underwent tracheostomy, among whom 4 patients are still alive. Mean duration of illness from onset to death (without tracheostomy) or tracheostomy was 6.8 years. Cause of death of patients who did not undergo tracheostomy was related to paresis of the larynx or pharynx, for example, aspiration pneumonia due to dysphagia, vocal cord paralysis and sudden death. Some of those who underwent tracheostomy deceased for causes which were not directly related to MSA such as cerebral hemorrhage or uremia, but others seem to be related to some problems of respiratory center such as central chronic respiratory failure, or sudden death (sometimes it happened after infection, but the obstruction of the respiratory tract was not always present at autopsy).

Age Factors↗