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PubMed2001

Videourodynamic and sphincter motor unit potential analyses in Parkinson's disease and multiple system atrophy.

OBJECTIVES: Urinary dysfunction is a prominent autonomic feature in Parkinson's disease (PD) and multiple system atrophy (MSA), which is not only troublesome but also a cause of morbidity in these disorders. Recent advances in investigative uroneurology offer a better insight into the underlying pathophysiology and appropriate management for urinary dysfunction. METHODS: twenty one patients with PD (15 men, six women, mean age 64 (49-76), mean disease duration 4 years (1-8 years), median Hoehn and Yahr grade 3 (1-4), all taking 300 mg/day of levodopa (100-500 mg)) and 15 with MSA (eight men, seven women, mean age 59 (48-72), mean disease duration 3 years (0.5-6 years)) were recruited. Videourodynamic and sphincter motor unit potential analyses in the patients with PD and MSA were carried out, looking for distinguishing hallmarks that might be useful in the differential diagnosis of these two diseases. RESULTS: Urinary symptoms were found in 72% of patients with PD and in 100% with MSA. Filling phase abnormalities in the videourodynamic study included detrusor hyperreflexia in 81% of patients with PD and 56% with MSA, and uninhibited external sphincter relaxation in 33% of patients with PD and 33% of those with MSA. However, open bladder neck at the start of filling was not seen in patients with PD but was present in 53% of those with MSA, suggestive of internal sphincter denervation. Sphincter motor unit potential analysis showed neurogenic motor unit potentials in 5% of patients with PD and in 93% of those with MSA, suggestive of external sphincter denervation. On voiding, detrusor-external sphincter dyssynergia was not seen in patients with PD but was present in 47% of those with MSA. Pressure-flow analysis showed that the Abrams-Griffiths number, a grading of urethral obstruction (outflow obstruction >40), in PD (40 in women and 43 in men) was larger than that in MSA (12 in women and 28 in men). Weak detrusor in PD (66% of women and 40% of men) was less common than that in MSA (71% of women and 63% of men). Postmicturition residuals >100 ml were absent in patients with PD but were present in 47% of patients with MSA. CONCLUSION: Patients with PD had less severe urinary dysfunction with little evidence of internal or external sphincter denervation, by contrast with the common findings in MSA. The findings of postmicturition residuals >100 ml, detrusor-external sphincter dyssynergia, open bladder neck at the start of bladder filling, and neurogenic sphincter motor unit potentials are highly suggestive of MSA.

Aged↗
PubMed2000

Complex motor disturbances in a sequential double lesion rat model of striatonigral degeneration (multiple system atrophy).

This study characterizes paw reaching, stepping and balance abnormalities in a double lesion rat model of striatonigral degeneration, the core pathology underlying levodopa unresponsive parkinsonism associated with multiple system atrophy. Extensive unilateral nigral or striatal lesions induced by 6-hydroxydopamine or quinolinic acid, respectively, produced a similarly marked contralateral paw reaching deficit without further deterioration following a secondary (complementary) lesion of ipsilateral striatum or substantia nigra. Contralateral stepping rates were reduced by unilateral 6-hydroxydopamine lesions without further deterioration following the secondary striatal lesion. In contrast, initial unilateral striatal quinolinic acid injections induced bilateral stepping deficits that significantly worsened contralaterally following the secondary nigral lesion. Contralateral sidefalling rates were significantly increased following primary nigral and striatal lesions. Secondary nigral but not secondary striatal lesions worsened contralateral sidefalling rates. Histological studies revealed subtotal (>90%) depletion of dopaminergic neurons in substantia nigra pars compacta and variable degrees of striatal degeneration depending on the lesion sequence. Animals pre-lesioned with 6-hydroxydopamine showed significantly larger residual striatal surface areas following the secondary striatal quinolinic acid lesion compared to animals with primary striatal quinolinic acid lesions (P<0.001). These findings are in line with previous experimental studies demonstrating that striatal dopamine depletion confers neuroprotection against subsequent excitotoxic injury. Whether loss of dopaminergic neurons protects against the striatal disease process occurring in multiple system atrophy (Parkinson-type) remains to be elucidated. In summary, this is the first experimental study to investigate spontaneous motor behaviour in a unilateral double lesion rat model. Our observations are consistent with a complex interaction of nigral and striatal lesions producing distinct behavioural and histological changes depending on the lesion sequence. Tests of forelimb akinesia and complex motor behaviour appear to provide a reliable tool that will be helpful for monitoring the effects of interventional strategies such as embryonic neuronal transplantation in the rat model of striatonigral degeneration.

Animals↗
PubMed2005

Therapeutic strategies in multiple system atrophy.

This review provides an update on therapeutic principles and their implications for practical management in multiple system atrophy (MSA), a sporadic neurodegenerative disorder characterized clinically by various combinations of dysautonomia, Parkinsonism, or cerebellar ataxia, often associated with other warning features (red flags), and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in selected multiple regions of the brain and spinal cord. Because of the small number of randomized controlled trials, the management of MSA is largely based on empirical or open-label evidence. Parkinsonism often shows a poor or unsustained response to chronic levodopa therapy, although more patients than previously recognized may experience an initial moderate-to-good dopaminergic response. There is no effective drug treatment for cerebellar ataxia. However, features of dysautonomia such as orthostatic hypotension, urinary retention or incontinence, constipation, and impotence, may often be relieved if recognized by the treating physician. Because no drug treatment consistently benefits patients with this disease in the long-term, palliative therapies are all the more important. Novel symptomatic and neuroprotective therapies are urgently required.

Adrenergic alpha-Antagonists↗
PubMed1999

T1 and T2 in the brain of healthy subjects, patients with Parkinson disease, and patients with multiple system atrophy: relation to iron content.

PURPOSE: To investigate the potential of magnetic resonance imaging for identification and quantification of brain iron in healthy subjects, patients with Parkinson disease, and patients with multiple system atrophy. MATERIALS AND METHODS: Forty-nine subjects were studied at 1.5 T. Regional T1 and T2 values were compared among groups and also with histopathologic estimates of iron concentration. RESULTS: In healthy subjects, interregional T1 and T2 differences in the cortex and basal ganglia showed a good correlation with reported values for iron concentration, and intraregional variations were generally consistent with reported variability of iron concentration. Patients with multiple system atrophy had T1 and T2 shortening in the globus pallidus consistent with reported increases in ferritin-bound iron and changes in the putamen consistent with accumulation of hemosiderin (posterior portion) and neuromelanin (remainder). Both groups of patients had changes in the cortex that are consistent with decreased ferritin concentration and T2 changes in white matter consistent with demyelination. Patients with Parkinson disease also had a (nonsignificant) T2 shortening in the substantia nigra that was suggestive of iron accumulation. CONCLUSION: Most of the T1 and T2 findings appear to be related to changes in iron content and form and may possibly be used as indicators of such changes.

Aged↗
PubMed1995

Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson's disease.

OBJECTIVE: The clinical recognition of multiple system atrophy (MSA) in patients presenting with parkinsonian signs is difficult. We attempted to verify the predictive value of some pointers that are used in clinical practice. DESIGN: Sixteen consecutive patients with pathologically confirmed MSA who presented with a parkinsonian syndrome over an 8-year period were studied retrospectively, and their clinical features were analyzed in detail. SETTING: Parkinson's Disease Society, Brain Tissue Bank, Institute of Neurology, London, England. PATIENTS: Sixteen patients with pathologically proven MSA who presented with parkinsonian syndrome in the first 3 years since disease onset. METHODS: Clinical features that were analyzed included the rapidity of disease progression, the relative symmetry of symptom onset, the presence or absence of tremor at initial presentation, the therapeutic response to levodopa and the associated presence of autonomic dysfunction. Fourteen of the 16 patients also had a computed tomographic scan of the brain performed. The frequency of selected items in MSA was compared with that found in 20 pathologically confirmed cases of Parkinson's disease and 16 pathologically confirmed cases of progressive supranuclear palsy (Steele-Richardson-Olszewski disease). RESULTS: It was found that a probability scale based on five selected items discriminated MSA with a pure parkinsonian presentation from Parkinson's disease, but not from progressive supranuclear palsy. Patients affected by the latter disorder, however, commonly presented with additional clinical features (supranuclear vertical down-gaze palsy, axial dystonia, and cognitive impairment), which helped to differentiate it from MSA.

Autonomic Nervous System Diseases↗
PubMed1987

Somatic and autonomic function in progressive autonomic failure and multiple system atrophy.

We studied 62 consecutive patients with progressive autonomic failure (PAF) or multiple system atrophy (MSA) (26 PAF; 36 MSA). Patients were well matched in age (67 vs 66 years), duration (39 vs 36 months), and severity of autonomic failure (median values for PAF and MSA). Peripheral somatic neuropathy occurred in 2 patients with PAF and 7 patients with MSA. Postganglionic sudomotor and vasomotor functions were studied using the quantitative sudomotor axon reflex test and supine plasma norepinephrine. The extent and severity of autonomic failure were assessed by the thermoregulatory sweat test, by heart rate responses to deep breathing and the Valsalva maneuver, and by blood pressure recordings. Severe and widespread anhidrosis was found in both PAF and MSA patients. Postganglionic sudomotor failure occurred at the forearm in 50% each of PAF and MSA patients and at the foot in 69% and 66% of PAF and MSA patients, respectively. However, postganglionic sudomotor function was preserved in some patients with anhidrosis on thermoregulatory sweat test, indicating a preganglionic lesion. Vagal abnormalities were found in 77% and 81% of PAF and MSA patients. Supine plasma free norepinephrine values were significantly reduced in PAF (p less than 0.001), but not in MSA, patients. Standing plasma norepinephrine values were reduced in both PAF (p less than 0.001) and MSA (p less than 0.001) patients. We conclude the following: (1) PAF is characterized by combined postganglionic sudomotor and adrenergic failure. (2) MSA is associated with a similar frequency of postganglionic sudomotor failure, but postganglionic adrenergic denervation was uncommon. (3) Preganglionic neuron is also involved in both disorders, but more severely in MSA. (4) Somatic neuropathy may occur.

Adolescent↗
PubMed1989

CSF acetylcholinesterase levels are reduced in multiple system atrophy with autonomic failure.

Diminished CSF levels of acetylcholinesterase in patients with multiple system atrophy attended by autonomic failure suggest that CNS cholinergic involvement may occur in this disorder. The lack of correlation between the low enzyme levels and low CSF levels of monoamine metabolites in these patients indicates that the acetylcholinesterase reduction is not directly related to disruption in these neurotransmitter systems. Normal CSF acetylcholinesterase levels in those patients with pure autonomic failure are consistent with functional integrity of central cholinergic pathways and support a pathophysiologic involvement limited to the peripheral nervous system.

Acetylcholinesterase↗
PubMed1995

[MRI study of degenerative process in multiple system atrophy].

The characteristic morphological changes of the brainstem and cerebellar regions of multiple system atrophy (MSA) were studied by MRI in varying subtypes, that is olivoponto cerebellar atrophy (OPCA: 23 cases), striatonigral degeneration (SND: 7 cases) and Shy-Drager's syndrome (SDS: 9 cases). OPCA was characterized by atrophy of the entire regions of the brainstem and the cerebellum. SND and SDS tended to show atrophy similar in type but lessin extent to OPCA. The common lesions in MSA were atrophy of the pontine base and cerebellum, and dilation of the fourth ventricle. Atrophy of the pontine base was more dominant in the inferior part than in the superior part, and cerebellar atrophy was more dominant in the superior part than in the inferior part, indicating that degeneration of the pontocerebellar pathway proceeds principally along fibers connecting the inferior part of the pons and the superior part of the cerebellum. Dilation of the fourth ventricle indicated atrophy of the middle cerebellar peduncle. In almost all the cases of OPCA and about a half the cases of SND and SDS, the pontine base and the middle cerebellar peduncle appeared as high signal intensity on T2 weighted image and as low intensity on T1, suggesting degeneration and demylination. In a few cases of OPCA, the dorsolateral part of the putamen were demonstrated as low signal intensity on T2 weighted image.

Adult↗
PubMed1994

[Clinical and MRI correlation in multiple system atrophy].

By using magnetic resonance imaging (MRI), we studied 11 patients with multiple system atrophy (MSA): 5 olivo-pontocerebellar atrophy (OPCA), 2 Shy-Drager syndrome (SDS), and 4 striatonigral degeneration (SND). The diagnoses of OPCA, SDS and SND were clinically made. The MR images were performed on 1.5 tesla MRI unit (Siemens Asahi Medical, Magnetom H15), using a T2-weighted spin echo (SE) sequence (TR: 2000-3000ms, TE: 80-90ms), a T1-weighted SE sequence (TR: 550, TE: 15), and a proton density-weighted (PD) SE sequence (TR: 2000-3000, TE: 12-22). In the patients with OPCA, MRI revealed cerebellar and brainstem atrophy and degeneration of pontine transverse fibers more marked than in the patients with SDS and SND. T2-weighted images showed low intensity in posterolateral putamina in one OPCA patient and all of SDS and SND patients. PD images demonstrated the abnormal slit-like high signals in posterolateral putamina in three SND. The degree of cerebellar ataxia was not well correlated with cerebellar and brainstem atrophy and degeneration of pontine transverse fibers. There was a positive correlation between the atrophy of cerebellum and brainstem and the duration of cerebellar ataxia. In most of the patients with parkinsonism, MRI demonstrated abnormal low signals in putamina on T2-weighted images. There were positive correlations between the abnormal low signals putamina and the duration and severity of parkinsonism. Though abnormal low signals in lateral putamina may be seen in normal aging and other disorders on T2-weighted images, it is useful to evaluate parkinsonism in MSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2005

In vitro models of multiple system atrophy.

alpha-Synuclein represents the major constituent of oligodendroglial cytoplasmic inclusions, the hallmark lesion of multiple system atrophy (MSA), a progressive disorder that is associated with selective degenerative cell loss in basal ganglia, cerebellum, brainstem, and spinal cord. The role of abnormal alpha-synuclein aggregation in oligodendroglial cells is still obscure, in particular, whether alpha-synuclein might impair oligodendroglial and, secondarily, neuronal integrity of those cells in the diseased brain. In an attempt to answer some of these questions, we have developed an "in vitro model of MSA" by expressing the wild-type or C-terminally truncated form of alpha-synuclein in glial cell cultures. With this simplified system, we have demonstrated that alpha-synuclein significantly affects the survival of glia and its vulnerability to environmental stress, which might represent a major step in the pathogenesis of MSA.

Basal Ganglia↗
PubMed2000

Magnetic resonance imaging distinguishes progressive supranuclear palsy from multiple system atrophy.

To establish diagnostic magnetic resonance imaging (MRI) criteria for differentiating progressive supranuclear palsy (PSP) from multiple system atrophy (MSA), magnetic resonance images from eight patients with probable PSP, 30 with probable MSA (nine striatonigral degeneration (MSA-P) and 21 olivopontocerebellar atrophy (MSA-C)), and ten age-matched controls were retrospectively studied. Anteroposterior diameters in the midline sagittal T1-weighted image of the rostral (RMT) and caudal midbrain tegmentum (CMT), caudal pons and medulla were measured. Divergence of the red nuclei (RN) in the axial T2-weighted image was judged. All PSP images had a smaller RMT diameter than the lower limit of the normal range, showed RN divergence, and had a pontine diameter within the normal range. All MSA images had a CMT diameter within the normal range; no MSA images showed divergence of RN. Forty-four percent (4/9) of MSA-P and 76% (16/21) of MSA-C images had a pontine diameter smaller than the lower limit of the normal range. On basis of the results, we propose MRI diagnostic criteria for differentiating PSP from MSA.

Age of Onset↗
PubMed2001

[Diagnosis and therapy of multiple system atrophy].

Numerous studies of the past years have established the clinical features, course and neuropathology characterizing multiple system atrophy (MSA). Clinically, two motor subtypes can be classified based on the predominance of a parkinsonian syndrome refractory to L-dopa and cerebellar ataxia. 80% of the cases involve MSA-P (the parkinsonian variant of MSA) and 20% MSA-C (cerebellar variant of MSA). Virtually all of these patients show disturbances of autonomic and urogenital function, half of the patients also exhibit pyramidal signs. Neuropathologically, MSA-C is based on an olivopontocerebellar atrophy (OPCA) and MSA-P on striatonigral degeneration (SND). However, a combination of OPCA and SND pathologies is observed in most cases. Recent evidence suggests that a key pathogenetic role may be played by glial alpha synuclein-containing inclusion bodies, which might lead to neuronal dysfunction and ultimately to cell loss. There is no therapy known to be effective in treating the motor disorders of MSA-C. By contrast, L-dopa replacement is at least transiently effective in about 30% of patients with MSA-P. Currently, initial efforts are being undertaken throughout Europe to develop neuroprotective solutions. Experiments are underway to test whether neurotransplantation by striatal grafting is a suitable method for inducing a clinically relevant response to L-dopa. Neurologically, the options for treating orthostatic hypertension and urogenital disorders are often overlooked.

Brain↗
PubMed2005

Interleukin-8, intercellular adhesion molecule-1 and tumour necrosis factor-alpha gene polymorphisms and the risk for multiple system atrophy.

In a case-control study using a clinically well-defined group of 41 multiple system atrophy (MSA) patients and 93 control subjects, the interleukin (IL)-8 (-251) TT genotype was associated with an approximately fourfold increased risk for MSA and, furthermore, this risk increased elevenfold with the simultaneous presence of the intercellular adhesion molecule-1 (ICAM-1: E469K) KK genotype, suggesting a gene-gene interaction. These data support a role for inflammation-related genes in risk for MSA.

Adult↗
PubMed2006

Multiple system atrophy is distinguished from idiopathic Parkinson's disease by the arginine growth hormone stimulation test.

OBJECTIVE: Multiple system atrophy (MSA) may be difficult to distinguish from idiopathic Parkinson's disease (PD). Our aim was to evaluate the accuracy of the arginine growth hormone (GH) stimulation test in distinguishing between MSA and PD in large populations of patients. METHODS: We measured the GH response to arginine in 69 MSA (43 MSAp [parkinsonism as the main motor feature] and 26 MSAc [cerebellar features predominated]) patients, 35 PD patients, and 90 healthy control subjects. We used receiver-operating curve analysis to establish the arginine cutoff value that best differentiated between MSA and PD. RESULTS: The GH response to arginine was significantly lower (p < 0.01) in MSA than in either PD patients or control subjects. At a cutoff level of 4 microg/L, arginine distinguished MSAp from PD with a sensitivity and specificity of 91% and MSAc from PD with a sensitivity of 96% and specificity of 91%. The arginine test had a positive predictive value for MSA of 95%. The GH response to arginine was not affected by disease duration or severity, MSA motor subtype, pyramidal signs, response to dopaminergic therapy, or magnetic resonance imaging findings. INTERPRETATION: The GH response to arginine differentiates MSA from PD with a high diagnostic accuracy. The results suggest an impairment of cholinergic central systems modulating GH release in MSA.

Antiparkinson Agents↗
PubMed2001

No functional effects of embryonic neuronal grafts on motor deficits in a 3-nitropropionic acid rat model of advanced striatonigral degeneration (multiple system atrophy).

Intrastriatal injection of 3-nitropropionic acid results in secondary excitotoxic local damage and retrograde neuronal cell loss in substantia nigra pars compacta, thus mimicking salient features of striatonigral degeneration, the core pathology underlying Parkinsonism associated with multiple system atrophy. We used 3-nitropropionic acid to create a rat model of advanced striatonigral degeneration in order to assess the effects of embryonic allografts upon rotational and complex-motor behavioural abnormalities. Following stereotaxic intrastriatal administration of 500nmol 3-nitropropionic acid in male Wistar rats we observed consistent amphetamine- and apomorphine-induced ipsiversive rotation. Furthermore, there were marked deficits of contralateral paw reaching. Subsequently, animals received intrastriatal implantations of either E14 mesencephalic or striatal or mixed embryonic cell suspensions. In addition, one group received sham injections. Grafted rats were followed for up to 21 weeks and repeated behavioural tests were obtained during this period. Drug-induced rotation asymmetries and complex motor deficits measured by paw reaching tests were not compensated by embryonic grafts. Persistence of drug-induced rotations and of paw reaching deficits following transplantation probably reflects severe atrophy of adult striatum, additional nigral degeneration as well as glial demarcation of embryonic grafts. We suggest that dopamine rich embryonic grafts fail to induce functional recovery in a novel 3-nitropropionic acid rat model of advanced striatonigral degeneration (multiple system atrophy).

Animals↗
PubMed1995

Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria.

To evaluate the possibility that parkinsonian signs may be the only presenting feature of multiple system atrophy (MSA), parkinsonian patients were studied who had no atypical clinical signs and had no symptoms of autonomic dysfunction, but who reported that they had not experienced the anticipated good response to dopaminergic treatment. These stringent criteria identified 20 patients from a series of 298 consecutive parkinsonian outpatients. The following clinical pointers were analysed: (a) rate of disease progression; (b) symmetry of parkinsonian symptoms and signs; (c) occurrence of resting tremor during the first three years from onset. In addition, all patients underwent (d) acute and chronic challenge with dopaminergic drugs; (e) cardiovascular reflex autonomic function tests; (f) high field MRI. Rapid progression of disease was seen in 45% of patients, onset was symmetric in 25%, tremor was absent at onset in 70%, response to dopaminergic drug challenges was inadequate in 40%, abnormal cardiovascular reflexes occurred in 50%, and some abnormal MRI finding occurred in 35% of cases. Each of these features was equally weighted by giving to each patient a 0 to 6 point score corresponding to the number of abnormal findings. Fifteen patients scoring higher than 1 were considered at risk for having MSA: five of them were classified as clinically possible (score 2), six as clinically probable (score 3-4), and four patients were classified as clinically definite multiple system atrophy (score 5). The six pointers considered were variably combined in each patient, none of them being universally abnormal in patients with high scores. The patients were followed up for a mean 2.1 (SEM 0.65) years. All but one of the 10 patients prospectively classified as probable or definite MSA developed unequivocal clinical signs of fully symptomatic MSA. A receiver operator characteristic cure was plotted for the prospective score based on follow up diagnosis. The best compromise for trade off between sensitivity and specificity was a cut off value at a score of 3. The sensitivity and specificity of the individual pointers considered to predict fully symptomatic MSA varied considerably, and no single item could predict whether patients presenting with just parkinsonian signs went on during the two year follow up period to develop fully symptomatic MSA. Instead, the number of abnormalities offered a predictive value for the clinical prognosis of these parkinsonian patients.

Adult↗