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[A case of multiple system atrophy presenting a regular involuntary movement of the neck muscles synchronous with respiration].

A patient with multiple system atrophy developed a regular, rhythmic involuntary movement of the neck muscles which appeared synchronous with respiration and could be described as "rocking-of-the-head". He had been treated with antiparkinsonian drugs such as L-dopa, L-dopa/carbidopa, amantadine hydrochloride and trihexiphenidyl hydrochloride for approximately one year. A fluoroscopic study assured that the involuntary "rocking-of-the-head" movement synchronized with the diaphragmatic up-and-down movement. A polygraphic study showed that the accelerometer curve which reflected the rocking movement of the head oscillated at approximately 0.7 Hz and synchronized with the surface EMG discharges of the right sternocleidomastoid muscle and the nasal flow curve. This involuntary movement was seen almost all day long as well as asleep but severest usually in the afternoon. Discontinuation of trihexiphenidyl hydrochloride alone made the involuntary movement less severe but never suppressed it completely. Resumption of the drug made the involuntary movement as severe as it had been. Discontinuation of L-dopa, L-dopa/carbidopa and amantadine hydrochloride was followed by disappearance of the involuntary movement in a day or so, in spite of continued intake of trihexiphenidyl hydrochloride. Rigidity and bradykinesia induced by discontinuation of these drugs, however, made it necessary to resume them. As a result the involuntary movement again exacerbated.

Amantadine↗

Brain magnetic resonance imaging in multiple-system atrophy and Parkinson disease: a diagnostic algorithm.

BACKGROUND: Brain magnetic resonance (MR) imaging offers the potential for objective criteria in the differential diagnosis of multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson disease (PD), since it frequently shows characteristic abnormalities in patients with MSA-P and is believed to be normal in patients with PD. OBJECTIVE: To determine concordance between clinical and MR imaging-based diagnoses of MSA-P and PD. DESIGN: Two neuroradiologists identified and rated striatal and infratentorial abnormalities in 39 brain MR images and assigned a diagnosis of PD, MSA-P, or MSA with additional marked cerebellar ataxia (MSA-C). SETTING: Academic medical center. PATIENTS: Thirty-nine patients with parkinsonism, including 21 with a clinical diagnosis of PD, 14 with MSA-P, and 4 with MSA-C. RESULTS: All patients with MSA and 14 (67%) of 21 patients with PD had some abnormality on brain MR imaging. Brainstem atrophy was seen in patients with MSA-P and MSA-C. Putaminal atrophy was seen only in MSA-P. Putaminal hypointensity and lateral slitlike hyperintensity were seen in both PD and MSA-P but were always mild in PD. Cerebellar abnormalities, seen in all patients with MSA-C and 11 patients with MSA-P, were also identified in 6 patients with PD, albeit always rated as mild. Nonconcordance between clinical and radiological diagnosis occurred in 2 patients with PD, 5 with MSA-P, and 1 with MSA-C. CONCLUSION: Since several features on brain MR imaging are seen only in MSA-P, a simple diagnostic algorithm may improve the MR imaging diagnosis of MSA-P and PD.

Adult↗

The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group.

The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.

Aged↗

SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy.

Conjugation of the small ubiquitin-like modifier, SUMO-1, to target proteins is linked to the regulation of multiple cellular pathways, including nucleocytoplasmic trafficking, cell cycle progression, the ubiquitin-proteasome system and apoptosis. Recently, the accumulation of SUMOylated proteins in pathological neuronal intranuclear aggregates has been found in several neurodegenerative diseases. The aim of our study was to examine SUMO-1 in the alpha-synucleinopathy diseases, Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). We conducted anti-SUMO-1 immunostaining of fixed brain tissue sections and smears of unfixed brain tissue homogenates of DLB and MSA cases. We found that oligodendroglial cytoplasmic inclusions, the alpha-synuclein-positive cytoplasmic aggregates that characterize MSA, exhibit robust punctate SUMO-1 immunostaining, marking discrete submicron-sized subdomains within the inclusion bodies. Lewy bodies in smears of DLB tissue homogenates showed similar SUMO-1-positive structures, although these were not detected in fixed tissue. In cell culture experiments, we found that the nuclear and perinuclear accumulation of SUMO-1 aggregates could be induced in glioma cells by chemical inhibition of proteasomal protein degradation.

Biomarkers↗

Disruption of spatial organization and interjoint coordination in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy.

Patients with basal ganglia diseases may exhibit ideomotor apraxia. To define the nature of the impairment of the action production system, we studied a repetitive gesture of slicing bread by three-dimensional computergraphic analysis in eight nondemented patients with Parkinson's disease in the "on" state, five with progressive supranuclear palsy and four with multiple system atrophy. Two patients with Parkinson's disease and two with progressive supranuclear palsy showed ideomotor apraxia for transitive movements on standard testing. A Selspott II system was used for kinematic analysis of wrist trajectories and angular motions of the shoulder and elbow joints. Patients with Parkinson's disease, progressive supranuclear palsy, and even some with multiple system atrophy exhibited kinematic deficits in the spatial precision of movement and velocity-curvature relationships; in addition, they failed to maintain proper angle/angle relationships and to apportion their relative joint amplitudes normally. Spatial disruption of wrist trajectories was more severe in patients with ideomotor apraxia. We posit that the basal ganglia are part of the parallel parieto-frontal circuits devoted to sensorimotor integration for object-oriented behavior. The severity and characteristics of spatial abnormalities of a transitive movement would therefore depend on the location and distribution of the pathologic process within these circuits.

Aged↗

Longitudinal change in REM sleep components in a patient with multiple system atrophy associated with REM sleep behavior disorder: paradoxical improvement of nocturnal behaviors in a progressive neurodegenerative disease.

A 60-year-old patient with multiple system atrophy (MSA) who presented with rapid eye movement (REM) sleep behavior disorder was investigated longitudinally by all-night polysomnography. REM sleep components, i.e. rapid eye movements and chin muscle activity, were analyzed together with the frequency of behaviors/movements on the videorecording. Decreased frequency of elaborate motor activity during REM sleep with time in this patient was compatible with the observation by his wife, and this change seemed to correlate with predominant tonic chin electromyogram with relatively suppressed phasic chin muscle activity, but the reduction of the REM sleep behavior disorder (RBD) episodes could be interpreted as being due to the increased rigidity along with MSA progression. The chronological change in REM sleep components in RBD with neurological disorders is worth studying in large follow-up series to enlarge our knowledge about the mechanism of behavioral manifestation of RBD in humans.

Brain Stem↗

Electromyography of the external anal sphincter in patients with Parkinson's disease and multiple system atrophy: frequency of abnormal spontaneous activity and polyphasic motor unit potentials.

Electromyographic studies of the external anal sphincter muscle have received increasing attention in the differential diagnosis of patients with parkinsonism. Based on the fact that the external anal sphincter muscle is partly innervated by fibers that originate in Onuf's nucleus in the segments S2-S4 of the spinal cord, an increased duration of the motor unit potentials (MUPs) and an increased polyphasia may reflect neuronal loss of these lower motor neurons characteristic for multiple system atrophy. We report the results of anal sphincter electromyography in 15 patients with clinically probable multiple system atrophy (MSA) and 10 patients with Parkinson's disease (PD). There was no significant difference between patients with MSA and patients with PD concerning the duration of MUPs, mean number of phases, and rate of polyphasic motor potentials. There was a tendency for a longer mean duration and increased polyphasia in patients with MSA compared to patients with PD. Spontaneous activity was recorded in 11 of 15 patients with MSA occurring especially in patients with MSA of the striatonigral type, but not in patients with PD. In this study, the duration of MUPs and the rate of polyphasia were unreliable criteria in the electrophysiological differential diagnosis of patients with parkinsonism. Abnormal spontaneous activity, although difficult to detect, is a more specific marker for neuronal degeneration of Onuf's nucleus occurring in patients with MSA.

Adult↗

Frequencies of single nucleotide polymorphism in alcohol dehydrogenase7 gene in patients with multiple system atrophy and controls.

A polymerase chain reaction and direct sequencing of the ADH7 gene were carried out in 50 controls and 50 patients with probable multiple system atrophy (MSA). Seven SNPs, one insertion, and one mismatch were found in patients with MSA and controls. There was no significant difference in the frequencies of each SNP between the patients and the controls (P > 0.05). Interpretation of this negative finding should be cautious in view of the relatively small number of cases.

Alcohol Dehydrogenase↗

R-R interval variation in Parkinson's disease and multiple system atrophy.

OBJECTIVE: To investigate whether the cardiac R-R interval variation (RRIV) is of value in differentiating patients with Parkinson's disease (PD) from multiple system atrophy (MSA). BACKGROUND: RRIV assessment is a simple procedure, reflecting mainly vagal efferent activity. Reduced RRIV was reported in MSA. METHODS: RRIV at rest and after 120 s of deep breathing was assessed blindly to clinical diagnosis in 22 PD and 20 MSA patients. The results were compared with data from 23 age-matched healthy subjects. RESULTS: RRIV at rest was 7.1 +/- 2.7% in PD and 9.7 +/- 7.2% in MSA, increasing after deep breathing to 11.2 +/- 6.3 and 12.3 +/- 6.6% correspondingly. The frequency of the RRIV abnormalities in the PD group (4/22, 18.2%) and MSA (6/20, 30%) were higher than among controls (P < 0.004). CONCLUSIONS: RRIV, either at rest or after deep breathing, may be abnormal both in PD and MSA, but does not distinguish between these disorders.

Aged↗

Blepharospasm associated with multiple system atrophy: a case report and review of the literature.

Although blepharospasm has been occasionally associated with parkinsonism, it has rarely been reported in patients with multiple system atrophy (MSA). We report a 65-year-old woman with MSA who developed blepharospasm seven years after onset, rendering her functionally blind. Clinical course and the findings of magnetic resonance imaging indicated cerebellar type MSA. The blink reflex studies showed prolonged R2 response and enhanced recovery cycle, indicating an increased excitability of the brainstem interneurons. These results suggest that pathophysiology of blepharospasm in MSA is similar to that of essential blepharospasm. Recognition of blepharospasm in MSA patients is important, as blepharospasm is a treatable feature in this otherwise intractable disorder.

Aged↗

Neuroendocrine responses to levodopa in multiple system atrophy (MSA).

Hypothalamic dopaminergic pathways are involved in the regulation of growth hormone and prolactin release from the anterior pituitary. Neuroendocrine studies in patients with multiple system atrophy (MSA), in whom there is a reported loss of hypothalamic dopamine, are few and contradictory. We therefore studied the neuroendocrine responses to 250 mg levodopa (plus 25 mg carbidopa) in subjects with MSA (n = 15), and compared them with age- and sex-matched healthy control subjects (n = 8). There were no significant differences in basal or post-levodopa levels of growth hormone (GH), growth hormone-releasing hormone (GHRH), glucose, insulin-like growth factor (IGF-1), or thyroid-stimulating hormone (TSH) between the groups. In patients with MSA, basal levels of prolactin were elevated (21.1 +/- 5.2 ng/mL [mean +/-standard error]) compared with control subjects (12.1 +/- 1.7, p <0.05), and after L-dopa there was increased variability in prolactin response with less suppression compared with control subjects. In conclusion, in patients with MSA, the GHRH and GH responses to L-dopa were preserved and were similar to responses in age-matched control subjects. In contrast, there was impaired dopaminergic suppression of prolactin secretion. In patients with MSA this may represent a selective dysfunction, rather than generalized loss, of tubero-infundibular dopaminergic neurones.

Adult↗

Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson's disease.

BACKGROUND: Formal laboratory testing of autonomic function is reported to distinguish between patients with Parkinson's disease and those with multiple system atrophy (MSA), but such studies segregate patients according to clinical criteria that select those with autonomic dysfunction for the MSA category. OBJECTIVE: To characterise the profiles of autonomic disturbances in patients in whom the diagnosis of Parkinson's disease or MSA used criteria other than autonomic dysfunction. METHODS: 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features. They were classified clinically into three diagnostic groups: Parkinson's disease (19), MSA (14), and uncertain (14). The performance of the patients with Parkinson's disease was compared with that of the MSA patients on five autonomic tests: RR variation on deep breathing, heart rate changes with the Valsalva manoeuvre, tilt table testing, the sudomotor axon reflex test, and thermoregulatory sweat testing. RESULTS: None of the tests distinguished one group from the other with any statistical significance, alone or in combination. Parkinson's disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions. CONCLUSIONS: This study supports the clinical observation that Parkinson's disease is often indistinguishable from MSA when it involves the autonomic nervous system. The clinical combination of parkinsonism and dysautonomia is as likely to be caused by Parkinson's disease as by MSA. Current clinical criteria for Parkinson's disease and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.

Aged↗

Olfactory dysfunction in cerebellar ataxia and multiple system atrophy.

BACKGROUND: Olfactory dysfunction has been reported in Parkinson's (PD) and Alzheimer's disease (AD). OBJECTIVE: 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. RESULTS: 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. CONCLUSIONS: 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.

Cerebellar Ataxia↗

CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson's disease.

BACKGROUND: In early disease stages it can be clinically difficult to differentiate idiopathic Parkinson's disease (IPD) from patients with multiple system atrophy predominated by parkinsonism (MSA-P). METHODS: In CSF of 31 patients with IPD, 19 patients with MSA-P, we analyzed tau, neurofilament light chain (NFL) and heavy chain (NFHp35) and the noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). RESULTS: CSF levels of NFL, NFHp35, and tau were significantly increased in MSA-P (all p<0.0001), whereas, MHPG levels were significantly decreased in MSA-P (p<0.0001). Optimal discriminative cut-off values for the differentiation between MSA-P and IPD were calculated resulting in high sensitivity (76-94%) and specificity (83-97%) levels. Multivariate logistic regression resulted in the combination of NFL and tau as independent contributors in differentiating between MSA-P and IPD. DISCUSSION: Higher CSF levels of axonal biomarkers could reflect advanced axonal degeneration in MSA-P. Differentiating MSA-P from IPD could be accurately possible with CSF analysis of a combination of axonal and neurotransmitter biomarkers.

Adult↗

Reduced cerebellar vermis activation during urinary storage and micturition in multiple system atrophy: 99mTc-labelled ECD SPECT study.

Single-photon emission computed tomography brain imaging with special reference of bladder function was performed in eight multiple system atrophy (MSA) patients (two men, six women; mean age, 61 years) and age-matched five normal control subjects (three men, two women; 62 years). In both groups imagings were obtained in three conditions; empty bladder, storage, and micturition. [99mTc]-labelled ECD (555 MBq) was intravenously injected, which was immediately trapped and stabilized within the brain. Using NEUROSTAT software, which could also cancel morphologic differences between MSA and canonical brain, statistical difference between normalized mean tracer counts of both groups in each phase was calculated and visualized. In the storage phase, there was a significant decrease in tracer activity in bilateral cerebellar vermis, particularly of the right side in the MSA group (P < 0.05), which is also known to be involved in the neural control of micturition. In the micturition phase, the area of decrease in tracer activity in the cerebellar vermis became wider in the MSA group. In the resting state, no statistically significance was seen between both groups. In conclusion, it is suggested that the decrease in tracer activity in the cerebellar vermis during urinary storage and micturition is contributing to the micturitional disturbance in this disorder.

Aged↗

Joint and skeletal deformities in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

The objective of this study is to characterize clinical features of joint and skeletal deformities in Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Clinical information including age, gender, presence of deformity, initial symptom side, neuropsychological and motor features, family history, and treatment with levodopa/dopamine agonists was collected on consecutive patients with PD, MSA, and PSP evaluated at the Movement Disorders Clinic at Baylor College of Medicine. In this series of 202 patients, 36.1% had deformities of the limbs, neck, or trunk, including 33.5% of PD, 68.4% of MSA, and 26.3% of PSP patients. "Striatal" hand and foot deformities were present in 13.4%, involuntary trunk flexion in 12.9%, anterocollis in 9.4%, and scoliosis in 8.4% of all patients. Patients with these joint and skeletal deformities had higher mean Unified Parkinson's Disease Rating Scale scores (57.4 vs. 46.6; P < 0.01) and were more often treated with levodopa (69.9% vs. 50.4%; P < 0.01) than patients without deformity, independent of disease duration. Patients with striatal deformity were younger than patients without deformity (mean 60.4 vs. 68.6 years; P < 0.01), and they tended to have an earlier age of onset of initial parkinsonian symptoms (mean 54.7 vs. 62.5 years; P < 0.01). Furthermore, the side of striatal deformity correlated with the side of initial parkinsonian symptoms in all patients (100%) with striatal hand and in 83.3% of patients with striatal foot. Joint and skeletal deformities are common and frequently under-recognized features of PD, MSA, and PSP that often cause marked functional disability independent of other motor symptoms.

Female↗

Trace of diffusion tensor differentiates the Parkinson variant of multiple system atrophy and Parkinson's disease.

We have recently shown that diffusion-weighted magnetic resonance (MR) imaging (DWI) discriminates patients with the Parkinson variant of multiple system atrophy (MSA-P) from those with Parkinson's disease (PD) by regional apparent diffusion coefficients (rADC) in the putamen. Because rADCs measured in one direction may underestimate diffusion-related pathologic processes, we investigated the diffusivity in different brain areas by trace of diffusion tensor (Trace(D)) in a new cohort of patients with MSA-P and PD. We studied 11 MSA-P, 17 PD patients, and 10 healthy volunteers matched for age and disease duration. Regional ADCs in three orthogonal directions and Trace(D) values were determined in selected brain regions including the basal ganglia, gray matter, white matter, substantia nigra, and pons. MSA-P patients had significantly higher putaminal and pallidal rTrace(D) values as well as rADCs in y- and z-direction than both PD patients and healthy volunteers. Moreover, putaminal Trace(D) discriminated completely MSA-P from both PD and healthy volunteers. The rADCs in the y- and z-direction provided a complete or near complete separation. In conclusion, our study confirms the results of previous studies of our group that patients with MSA-P show an increased putaminal diffusivity due to neuronal loss and gliosis. Because rADCs in one direction are dependent on the slice orientation relative to the directions of fiber tracts, Trace(D) imaging appears to be more accurate in the separation of MSA-P from PD.

Aged↗

Distribution of cerebellar cortical lesions in multiple system atrophy: a topographic neuropathological study of three autopsy cases in Japan.

We investigated neuropathologically the distribution of the cerebellar cortical lesions in three Japanese autopsy cases of multiple system atrophy (MSA) using hemisphere specimens. The lesions were classified as mild, moderate or severe. The distribution of cerebellar cortical lesions in all three cases were uniform: the cerebellar cortical lesions were more conspicuous in the vermis than in the hemisphere. These neuropathological findings differ from the established theory that cerebellar lesions of MSA are more pronounced in the hemisphere than in the vermis. The degree of cerebellar cortical lesions in our cases increased in relation to the duration of the disease. Our pathological data may contribute to the morphological differential diagnosis in various neurodegenerative disorders including late cortical cerebellar atrophy. Our neuropathological findings may also make a contribution to the neuroradiological progress in the differential diagnosis of spinocerebellar disease.

Brain Mapping↗