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PubMed2004

[Multiple system atrophy--update].

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder, showing various combination of progressive autonomic failure, cerebellar ataxia, and levodopa poorly responsive parkinsonism. MSA accounts for more than 40% of spinocerebellar ataxias in Japan. Pathologically, myelinopathy, neuronal loss and gliosis are the cardinal features in the brain of MSA. In addition, excessive accumulation of alpha-synuclein, mostly in oligodendroglia and partly in neuron, characterizes the cellular pathology of the disorder. However, mechanism causing the disorder is not known. Clinical diagnosis of MSA is based on Quinn's criteria or, more recently, on Consensus Criteria. In Japan, criteria of the Research Committee of Ataxic Diseases, the Ministry of Health and Welfare of Japan, was popular, and it contributed to the research base on MSA. Besides the major manifestations incorporated into those criteria, various dystonic manifestation, rhythmic myoclonus, emotional incontinence, sleep disturbance, sleep-related movement disturbances, and signs of vasomotor dysfunction, provide aids in the differential diagnosis of MSA. In neuroimaging studies, not only MRI but dopamine transporter and D2 receptor imaging by SPECT also contribute to the diagnosis of MSA. These laboratory diagnostic procedures can contribute to improve reliability of the diagnosis, and needs to be taken into account when preventive measures become available.

Humans↗
PubMed1999

[Sleep apnea syndromes in multiple system atrophy].

Multiple-system atrophy (MSA) is characterized by progressive autonomic failure with cerebellar, pyramidal and extrapyramidal signs. In MSA patients laryngoscopy often reveals unilateral or bilateral abductor vocal fold palsies. Snoring is very common. However, assessment of sites of obstruction and their severity is needed. We report our clinical experience in managing a 56-year-old, obese male MSA patient (1.76 m height, 100 kg weight, BMI 32.3 kg/m2) who was admitted for evaluation of snoring and excessive daytime sleepiness. Endoscopy while awake demonstrated an incomplete abductor vocal fold palsy. Polysomnography confirmed heavy snoring with arousals (11.1/h) and an RDI of 1.4/h. Sleep efficiency was low (51.9%) due to long intermittent awake periods. Sleep videoendoscopy of the upper airway proved the entire pharynx to be open during REM and non-REM sleep. During inspiration fluttering movements of the vocal cords caused the snoring. This was regularly terminated by arousals. The further treatment is discussed. In general, glottic snoring without daytime stridor is rare and has only been described in MSA patients. However, certain of these patients will also be pharyngeal snorers. The source of the sound and site of obstruction can only be diagnosed by sleep videoendoscopy.

Comorbidity↗
PubMed2006

Health-related quality of life in multiple system atrophy.

Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

Anxiety↗
PubMed2000

Cerebral atrophy in multiple system atrophy by MRI.

Cranial magnetic resonance images (MRI) of the cerebral areas of 40 patients with multiple system atrophy (MSA) and of 61 age-matched controls were analyzed. The cerebral area of MSA patients was 131. 95+/-15.89 cm(2) (mean+/-S.D.), which was significantly smaller than that of normal controls at 149.01+/-10.93 cm(2) (P<0.0001). All 23 MSA cases subjected to the MRI study over a 1-year period showed progressive cerebral atrophy, and the atrophy rate was 2.46+/-1. 66%/year. There were no significant differences within the MSA subtypes or between gender. The progression of cerebral atrophy in MSA correlated more with duration (r=-0.634) than age (r=-0.421). We conclude that MRI findings throughout the course of MSA suggest progressive cerebral atrophy, which is common in all subtypes and reflects duration of the disease rather than age.

Aged↗
PubMed2005

An autopsy case of early ("minimal change") olivopontocerebellar atrophy (multiple system atrophy-cerebellar).

We report a 57-year-old woman with multiple system atrophy (MSA) of 15-month duration. The patient developed dysarthria, followed by impaired balance of gait, mild limb ataxia, and saccadic eye movement. A postmortem examination performed after she was found dead in a bathtub revealed neuronal loss restricted to the olivopontocerebellar system, being more severe in the pontine nucleus. Mild neuronal loss was also found in the anterior vermis and inferior olivary nucleus. Alpha-synuclein immunohistochemistry demonstrated widespread occurrence of glial cytoplasmic inclusions in the central nervous system, which were more numerous in the pontine base and cerebellar white matter. In contrast, neuronal alpha-synuclein accumulation was confined to the pontine and inferior olivary nuclei. The number of neuronal intranuclear inclusions was much higher than that of neuronal cytoplasmic inclusions. Moreover, alpha-synuclein accumulation was more severe in the neurites than in the cytoplasm or nucleus. This case demonstrates the early pattern of brain pathology in MSA-cerebellar (olivopontocerebellar atrophy).

Brain↗
PubMed1995

Positron emission tomography studies on the dopaminergic system and striatal opioid binding in the olivopontocerebellar atrophy variant of multiple system atrophy.

Ten patients with sporadic olivopontocerebellar atrophy and autonomic failure were studied with positron emission tomography. Subjects underwent both an [11C]diprenorphine and an [18F]fluorodopa scan. The mean caudate-occipital uptake ratio for [11C]diprenorphine was significantly reduced to 88% and the putamen-occipital uptake ratio to 85% of the control values. Individually, 4 of the 10 patients had significantly reduced opioid binding in the putamen. Mean putamen [18F]fluorodopa uptake was significantly diminished (to 71% of the control mean); individually 7 patients had significantly reduced uptake. There was a significant positive correlation between putamen-occipital uptake ratios for [11C]diprenorphine and putamen uptake of [18F]fluorodopa. Our results suggest that subclinical nigrostriatal dysfunction is present in the majority of patients with sporadic olivopontocerebellar atrophy, in accordance with it being part of the spectrum of multiple system atrophy.

Autonomic Nervous System Diseases↗
PubMed2006

Altered venous capacitance as a cause of postprandial hypotension in multiple system atrophy.

Patients with multiple system atrophy (MSA) often have clinically significant postprandial hypotension (PPH). To elucidate the cause of insufficient cardiac preload augmentation that underlies PPH, we recorded calf venous capacitance (CVC) by strain-gauge plethysmography, in 17 MSA patients and eight healthy controls before and after oral glucose ingestion. Among 17 MSA patients, nine who showed a decrease in systolic blood pressure exceeding 20 mmHg and were diagnosed with PPH. MSA patients without PPH showed a significant decrease in CVC and a significant increase in cardiac output after oral glucose ingestion, as did controls; those with MSA exhibiting PPH showed a significant increase in CVC and no significant change in cardiac output. The change in CVC correlated positively with the decrease in systolic and diastolic blood pressure after glucose ingestion, and also correlated negatively with the increase in cardiac output. Physiologically, PPH is prevented by a decrease in venous capacitance, which increases circulating blood volume and cardiac output. In some MSA patients, failure of venous capacitance to decrease may induce PPH.

Aged↗
PubMed2004

The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations.

Multiple system atrophy (MSA) has varying clinical (MSA-P versus MSA-C) and pathological [striatonigral degeneration (SND) versus olivopontocerebellar atrophy (OPCA)] phenotypes. To investigate the spectrum of clinicopathological correlations, we performed a semi-quantitative pathological analysis of 100 MSA cases with well-characterized clinical phenotypes. In 24 areas, chosen from both the striatonigral (StrN) and olivopontocerebellar (OPC) regions, the severity of neuronal cell loss and gliosis as well as the frequency of glial (oligodendroglial) cytoplasmic inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs) were determined. Clinical information was abstracted from the patients' medical records, and the severity of bradykinesia in the first year of disease onset and in the final stages of disease was graded retrospectively. The degree of levodopa responsiveness and the presence or absence of cerebellar ataxia and autonomic symptoms were also recorded. We report that 34% of the cases were SND- and 17% were OPCA-predominant, while the remainder (49%) had equivalent SND and OPCA pathology. We found a significant correlation between the frequency of GCIs and the severity of neuronal cell loss, and between these pathological changes and disease duration. Our data also suggest that GCIs may have more influence on the OPC than on the StrN pathology. Moreover, we raise the possibility that a rapid process of neuronal cell loss, which is independent of the accumulation of GCIs, occurs in the StrN region in MSA. There was no difference in the frequency of NCIs in the putamen, pontine nucleus and inferior olivary nucleus between the SND and OPCA subtypes of MSA, confirming that this pathological abnormality is not associated with a particular subtype of the disease. In the current large post-mortem series, 10% of the cases had associated Lewy body pathology, suggesting that this is not a primary process in MSA. As might be expected, there was a significant difference in the severity of bradykinesia and the presence of cerebellar signs between the pathological phenotypes: the SND phenotype demonstrates the most severe bradykinesia and the OPCA phenotype the more frequent occurrence of cerebellar signs, confirming that the clinical phenotype is dependent on the distribution of pathology within the basal ganglia and cerebellum. Putaminal involvement correlated with a poor levodopa response in MSA. Our finding that relatively mild involvement of the substantia nigra is associated clinically with manifest parkinsonism, while more advanced cerebellar pathology is required for ataxia, may explain why the parkinsonian presentation is predominant over ataxia in MSA.

Adult↗
PubMed2003

Multiple system atrophy: an update.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that usually manifests in the early sixth decade of life and progresses relentlessly with a mean survival of 9 years. Clinically, MSA is dominated by autonomic/urogenital failure, which may be associated with either levodopa (L-dopa) -unresponsive parkinsonism in 80% of cases (MSA-P subtype) or with cerebellar ataxia in 20% of cases (MSA-C subtype). Pathologically, MSA is characterized by a neuronal multisystem degeneration and abnormal glial cytoplasmic inclusions containing alpha-synuclein aggregates. Pharmacological treatment of motor features is disappointing except for a transient L-dopa response in a minority of MSA-P patients. In contrast, autonomic and urogenital features of MSA should be identified early on, because they can be treated effectively in many instances. Neuroprotective strategies are presently unavailable, however, two multicentre European trials have been launched to evaluate the effects of riluzole and human recombinant growth hormone on disease progression in MSA. Clearly, further randomised, controlled trials are required to identify effective symptomatic or neuroprotective agents in MSA. Several in vivo models have become available to allow a careful preselection of candidate agents. Several research groups have been formed in Europe (EMSA-SG, NNIPPS) and United States (NAMSA-SG), providing a framework for coordinated trial activity in MSA.

Animals↗
PubMed2000

Stridor and death in multiple system atrophy.

Patients with multiple system atrophy (MSA) have a mean survival of 8 to 10 years. Nocturnal stridor has been considered a poor prognostic feature. We analyzed demographic, clinical, and polysomnographic data and obtained follow-up information from 42 patients with MSA (30 with follow-up data) seen in a Sleep Disorders Center. Group I consisted of 17 patients with nocturnal stridor, including seven with daytime stridor. Group II consisted of 25 patients without stridor. Analysis of survival curves of 30 patients with follow-up information showed a significantly shorter survival from the sleep evaluation, but not from disease onset, for patients with stridor compared with those without. Nine of 11 patients with stridor died a median of 2 years from presentation and the only two survivors had undergone tracheostomy. Patients with daytime stridor and immobile vocal cords had especially poor prognoses. However, two of four patients with tracheostomies also died, as did six of 19 without stridor. We postulate that central hypoventilation and its complications may have been responsible for many of these other deaths. We conclude that stridor does carry a poor prognosis in patients with MSA but that there are also other causes of death. We recommend consideration of tracheostomy for patients with MSA who have stridor, but also assessment for central hypoventilation and appropriate management if it is present.

Aged↗
PubMedDate not supplied

Placebo-controlled trial of amantadine in multiple-system atrophy.

OBJECTIVE: Multiple-system atrophy (MSA) often presents as atypical parkinsonian syndrome with rapid progression and poor response to levodopa. Reports on the open-label use of amantadine in MSA suggest variable antiparkinsonian efficacy. The authors therefore conducted a double-blind, placebo-controlled crossover trial of amantadine in MSA patients. METHODS: Eight patients were enrolled in this study. They received either amantadine 200 mg twice daily or placebo for 3 weeks, followed by a 1-week washout and the alternate treatment of 3 weeks. Antiparkinsonian effects were evaluated using the Unified Parkinson's Disease Rating Scale part II (UPDRS-II, activities of daily living) and UPDRS-III (motor examination) before and at the end of each treatment phase. Timed tests were also performed according to the CAPIT protocol. RESULTS: There was a trend toward reduction of UPDRS-III scores during amantadine treatment (P = 0.058). Delta values of the treatment arm were higher than those of the placebo arm. However, this difference (-2.25 pt; 95% CI, -6.7-2.2) failed to reach significance. Reduction of UPDRS-III subscores for akinesia, rigidity, tremor, postural instability, and gait disorder failed to reach significance too. The hand-arm movement test revealed nonsignificant improvement in the amantadine arm. CONCLUSION: This study suggests that amantadine fails to provide clinically significant antiparkinsonian benefit to patients with MSA. The authors cannot exclude mild effects due to the limited sample size.

Aged↗
PubMed1999

Neural transplantation in animal models of multiple system atrophy: a review.

Multiple system atrophy of the striatonigral degeneration (MSA-SND) type is increasingly recognized as major cause of neurodegenerative parkinsonism. Due to combined degeneration of substantia nigra pars compacta (SNC) and of striatum, antiparkinsonian therapy based on levodopa substitution eventually fails in more than 90% of patients. Animal models of MSA-SND are urgently required as test-bed for the evaluation of novel therapeutic interventions in this disorder such as neurotrophic factor delivery and neuronal transplantation. A number of well established rodent and primate models of Parkinson's (PD) and Huntington's (HD) disease replicate either nigral ("PD-like") or striatal ("HD-like") pathology and may therefore provide a useful baseline for the development of MSA-SND models. Previous attempts to mimick MSA-SND pathology in rodents have included sequential injections of 6-hydroxydopamine (6OHDA) and quinolinic acid (QA) into medial forebrain bundle and ipsilateral striatum, respectively ("double toxin-double lesion" approach). Preliminary evidence in rodents subjected to such lesions indicates that embryonic transplantation may partially reverse behavioural abnormalities. Intrastriatal injections of mitochondrial toxins such as 3-nitropropionic acid (3NP) and 1-methyl-4-phenylpyridinium (MPP+) in rodents result in (secondary) excitotoxic striatal lesions and subtotal neuronal degeneration of ipsilateral SNC, thus producing MSA-SND-like pathology by a simplified "single toxin-double lesion" approach. Comparative studies of human SND pathology and rodent striatonigral lesions are required in order to determine the rodent model(s) most closely mimicking the human disease process.

Animals↗
PubMed1997

The "cold hands sign" in multiple system atrophy.

Patients with multiple system atrophy (MSA) often have cold, dusky, violaceous hands, with poor circulatory return after blanching by pressure. We therefore compared hand skin temperature in nine age-matched subjects with probable MSA, 10 with idiopathic Parkinson's disease (PD), and 10 healthy controls both at rest and following a standard cooling procedure. Baseline skin temperature in the MSA group was significantly lower than in both the PD and control groups, and four of the nine MSA patients were colder at baseline than the coldest control value. After cooling, the MSA group also showed a significantly greater reduction in skin temperature than the PD group. The rate of skin temperature recovery did not differ between the three groups, although the MSA group required more time to return completely to their baseline temperature. Changes in skin colour or temperature are easily detected, and suggest a defect in neurovascular control of distal extremities. The "cold hands sign" is another clinical "red flag" that helps to raise the suspicion of MSA.

Atrophy↗
PubMed1996

Ubiquitin-positive inclusions in different types of multiple system atrophy: distribution and specificity.

Multiple system atrophy (MSA) is a neurodegenerative disorder that encompasses different clinicopathological syndromes, either occurring alone or with a variable degree of overlap. Oligodendroglial, intracytoplasmic argyrophilic and ubiquitin-reactive inclusions are regarded as a histologic hallmark. We examined the distribution and specificity of these ubiquitin-reactive inclusions (UBRI) in 20 cases of MSA (7 cases of sporadic adult olivoponto-cerebellar atrophy [OPCA], 1 case of hereditary adult OPCA, 4 cases of infantile OPCA, 2 cases of Shy-Drager-Syndrome [SDS], 4 cases of striatonigral degeneration [SND] and 2 cases of non-classified atrophy of multiple systems) and 93 control cases with various disorders. Antibodies were used against ubiquitin, PGP 9.5, TAU-protein, glutathion-S-transferase (GST) and metallothionein (MT). Oligodendroglial UBRI were detected in all but 2 cases of sporadic adult MSA and 3 controls, whereas they were absent in hereditary and infantile OPCA. They could also be recognized with Gallyas stain and anti-TAU. Immunopositivity was also seen with GST (11 cases), PGP 9.5 (4 cases) and MT (1 case). Distribution of oligodendroglial UBRI, although not showing topographical linkage to neuronal degeneration in all cases, does not seem to occur in a haphazard pattern.

Adolescent↗
PubMed2000

The pathogenesis of multiple system atrophy: past, present, and future.

Multiple system atrophy is a sporadic, adult-onset neurodegenerative disease of unknown etiology. The condition may be unique among neurodegenerative diseases by the prominent, if not primary, role played by the oligodendroglial cell in the pathogenetic process. Recent developments in our understanding of multiple system atrophy have included the detection of glial cytoplasmic inclusions and alpha-synuclein accumulation in these inclusions. The latter finding links multiple system atrophy as an "alpha-synucleinopathy" to Parkinson's disease and dementia with Lewy bodies. This article reviews recent important findings of potential relevance to the pathogenesis of multiple system atrophy. We also speculate on areas in which further advances may be made to progress our understanding of this devastating condition.

Biomarkers↗
PubMed2001

Multiple system atrophy: cellular and molecular pathology.

Multiple system atrophy is an adult onset neurodegenerative disease, featuring parkinsonism, ataxia, and autonomic failure, in any combination. The condition is relentlessly progressive and responds poorly to treatment. Death occurs on average six to seven years after the onset of symptoms. No familial cases of multiple system atrophy have been reported, and no environmental factors have been robustly implicated as aetiological factors. However, analytical epidemiological studies are hampered because the condition is relatively rare. The discovery of the glial cytoplasmic inclusion (GCI) in 1989 helped to define multiple system atrophy as a clinicopathological entity, and drew attention to the prominent, if not primary, role played by the oligodendrocyte in the pathogenesis of the condition. Subsequently, GCIs were shown to be positive for alpha-synuclein, with immunostaining for this protein indicating that white matter pathology was more widespread than had previously been recognised. The presence of alpha-synuclein in GCIs provides a link with Parkinson's disease, dementia with Lewy bodies, and neurodegeneration with brain iron accumulation, type 1 (or Hallervorden-Spatz syndrome), in which alpha-synuclein is also found within Lewy bodies. This has led to the term "synucleinopathy" to embrace this group of conditions. The GCIs of multiple system atrophy contain a range of other cytoskeletal proteins. It is unknown how fibrillogenesis occurs, and whether there is primary oligodendrocytic dysfunction, which then disrupts the neurone/axon as a consequence of the glial pathology, or whether the oligodendrocytic changes merely represent an epiphenomenon. Further research into this devastating condition is urgently needed to improve our understanding of the pathogenesis, and also to produce new treatment approaches.

Aged↗