Intrathecal Baclofen Therapy Slows Progressive Disability in Multiple System Atrophy

Objectives: Evaluate the benefit of intrathecal baclofen (ITB) therapy on function, quality of life, and progression in patients with multiple system atrophy (MSA). Methods: We report on three MSA patients at different stages treated with ITB therapy. MSA patients were staged using Watanabe et al. ADL milestones for disease progression and by scales for tone (modified Ashworth scale) ambulation (Hauser ambulation index) and disability (expanded disability status scale) Results: All three patients had an improvement in the modified Ashworth scale and none had progression in their disability or ambulatory outcomes and did not progress as predicted by Watanabe et al. Conclusions: Our results suggest that ITB can maintain (or improve function) and maintain quality of life in patients with MSA. ITB is currently not indicated for patients with MSA but should be studied further for the quality of life benefits and delay in disease progression it potentially provides.     

The "Cross" Signs in Patients With Multiple System Atrophy: A Quantitative Study

Patients with multiple system atrophy (MSA) may show the "cross" sign in the pontine base that has been considered as an expression of the degeneration of pontine neurons and transverse pontocerebellar fibers. However, correlations between pontine base atrophy and existence of "cross" sign have not been fully investigated. The authors studied 68 patients with MSA (47 MSA-C [predominantly cerebellar ataxia], 21 MSA-P [predominantly parkinsonism], mean [+/-SD ] 58.7 +/- 10.9 years). T1-weighted (T1W) sagittal and axial images and T2-weighted (T2W) axial images were obtained for all patients and controls. To measure the areas of pontine basis and cerebellar vermis, the authors used midsagittal T1W images and analyzed a bit map transformed on a computer. They classified atrophy in the pontine base into 3 grades. There is significant correlation between atrophies of pontine base and existence of the cross sign. All patients with a smaller area of pontine base 2 standard deviations below those of normal controls had the cross sign. This supports that existence of the cross sign depends only on the extent of pontine base atrophies.     

Micturitional Disturbance in Multiple System Atrophy

Abstract: Detailed micturitional histories and urodynamic studies were conducted to investigate the micturitional disturbance in multiple system atrophy (MSA). Eighty-six patients with MSA comprised of 14 with striatonigral degeneration (SND), 42 with olivopontocerebellar atrophy (OPCA) and 30 with Shy-Drager syndrome (SDS). The results were as follows. Micturitional symptoms were noted in over 90% of patients with each type of MSA. Dominant symptoms were irritative ones in SND and OPCA, and a combination of irritative and obstructive ones in SDS. Micturitional symptoms in SDS appeared earlier than those in SND or OPCA. The degree of micturitional disturbance was severer in SDS than in SND or OPCA. Micturitional disturbance tended to become worse as the disease progressed. The responsible sites of lesions of micturitional disturbance seemed to be supra- as well as infranuclear lesions of the pelvic and pudendal nerves in MSA. Infranuclear lesions were more prominent in SDS than in SND or OPCA. Follow-up studies of some of the patients with SDS and OPCA suggested that the responsible sites of pelvic nerve lesions changed from supra- to infranuclear lesions during the course of disease.     

Multiple system atrophy (MSA) with massive macrophage infiltration in the ponto‐cerebellar afferent system

Multiple system atrophy (MSA) is characterized pathologically by a systemic degeneration of the olivopontocerebellar (OPC), striatonigral (SN) and autonomic systems. Massive glial cytoplasmic inclusions (GCIs) are specific for this disease. Massive lipid‐laden macrophage infiltration in the degenerating tracts has not been described up to now. We here report a case of MSA with this rare event in the ponto‐cerebellar (cerebellopetal) fibers. The patient, 54‐year‐old housewife, developed ataxia. At the age of 55 years, she was diagnosed as having MSA by cerebellar ataxia, extrapyramidal signs, autonomic failure and Horner syndrome. She died from asphyxia at the age of 57. The autopsy revealed OPC and SN system atrophy, degeneration and numerous GCIs, compatible with MSA. Numerous lipid‐laden macrophages were seen in the pontine nuclei and its transverse fibers including the white matter of the cerebellum, which has not been reported up to now. There was no macrophage infiltration in the other areas. Transient ischemia, infarction and wallerian degeneration do not account for this rare event. The ponto‐cerebellar (cerebellopetal) tract pathology, as observed by postmortem neuropathological study, may occur in the context of MSA.     

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.     

Spatial patterns of alpha-synuclein positive glial cytoplasmic inclusions in multiple system atrophy.

In cases of multiple system atrophy (MSA), glial cytoplasmic inclusions (GCI) were distributed randomly or present in large diffuse clusters (>1,600 microm in diameter) in most areas studied. These spatial patterns contrast with those reported for filamentous neuronal inclusions in the tauopathies and alpha-synucleinopathies.     

Deep Brain Stimulation of the Globus Pallidus Internus and Externus in Multiple System Atrophy

Background

Multiple system atrophy with parkinsonism (MSA-P) is a progressive condition with no effective treatment.

Objective

The aim of this study was to describe the safety and efficacy of deep brain stimulation (DBS) of globus pallidus pars interna and externa in a cohort of patients with MSA-P.

Methods

Six patients were included. Changes in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III), Parkinson's Disease Questionnaire (PDQ-39) scores, and levodopa equivalent daily dose were compared before and after DBS. Electrode localization and volume tissue activation were calculated.

Results

DBS surgery did not result in any major adverse events or intraoperative complications. Overall, no differences in MDS-UPDRS III scores were demonstrated (55.2 ± 17.6 preoperatively compared with 67.3 ± 19.2 at 1 year after surgery), although transient improvement in mobility and dyskinesia was reported in some subjects.

Conclusions

Globus pallidus pars interna and externa DBS for patients with MSA-P did not result in major complications, although it did not provide significant clinical benefit as measured by MDS-UPDRS III. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Somatic SNCA Copy Number Variants in Multiple System Atrophy are Related to Pathology and Inclusions

Background

Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains.

Objective

The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions.

Methods

We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP).

Results

We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions.

Conclusions

The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.