Version May 2024
INTRODUCTION — Multiple system atrophy (MSA) is a rare neurodegenerative disorder that pathologically involves the basal ganglia, brainstem, cerebellum, and spinal cord; it clinically presents with various combinations of autonomic dysfunction, parkinsonism, ataxia, and corticospinal degeneration.
MSA is one of several neurodegenerative disorders associated with alpha-synuclein aggregation, or synucleinopathies; others include Parkinson disease (PD) and dementia with Lewy bodies (DLB). MSA is also referred to as an atypical parkinsonian disorder based on distinct yet overlapping features with PD; other atypical parkinsonian disorders include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).
This topic will review the epidemiology, pathology, pathogenesis, and genetics of MSA. The clinical features, diagnosis, and treatment of MSA are reviewed separately. (See "Multiple system atrophy: Clinical features and diagnosis" and "Multiple system atrophy: Prognosis and treatment".)
HISTORY AND NOMENCLATURE — MSA is a unifying term that brings together a group of rare, fatal neurodegenerative syndromes that used to be referred to as olivopontocerebellar atrophy (OPCA), striatonigral degeneration, and Shy-Drager syndrome.
In 1900, Dejerine and Thomas provided the first report of sporadic OPCA, a disease that later would become a part of the spectrum of MSA [1]. Orthostatic hypotension as a manifestation of autonomic failure was described in 1925 [2], and in 1960, Shy and Drager reported patients with autonomic features of orthostatic syncope, impotence, and bladder dysfunction who went on to develop gait abnormalities, tremor, and fasciculations [3]. This disorder ultimately became known as the Shy-Drager syndrome. Also in 1960, the first cases of a predominantly akinetic and rigid parkinsonian syndrome were reported, which correlated pathologically with evidence of striatonigral degeneration [4].
In 1969, the term "multiple system atrophy" was introduced to encompass all three clinical syndromes, based on their similar pathology [5]. Striatonigral degeneration was later defined as MSA with predominant parkinsonism (MSA-P), while OPCA was defined as MSA with predominant cerebellar ataxia (MSA-C) [6]. Ultimately, glial cytoplasmic inclusions containing alpha-synuclein were identified as the pathologic hallmark of all three syndromes, and MSA was recognized as part of the pathologic family of neurodegenerative disorders termed "synucleinopathies" [7,8].
Beginning in the late 1990s, consensus groups developed clinical guidelines to define MSA, which were modified in 2008 and again in 2022 [6,9-12]. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Diagnostic criteria'.)
EPIDEMIOLOGY — MSA is a rare disease. The estimated annual incidence is 0.6 cases per 100,000 person-years [13]. In adults >50 years of age, the incidence increases to 3 per 100,000 person-years [14].
The estimated prevalence of MSA ranges from 2 to 5 cases per 100,000 population [13,15,16]. These estimates are approximately 10-fold lower compared with those of Parkinson disease (PD). (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Epidemiology'.)
The only established risk factor for MSA is advancing age. The median age of symptom onset is in the sixth decade, which is approximately five years younger than that of PD. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Age of onset'.)
Males and females are affected in approximately equal proportions [17-20], although some studies have reported a male predominance [21,22]. This finding may be secondary to earlier recognition of impotence as a major diagnostic feature in males.
There are no specific racial/ethnic predilections, and the disease has been reported worldwide. Rare families with MSA have been described, but the majority of cases appear to be sporadic. (See 'Genetics' below.)
There are no established environmental risk factors for MSA, although data are limited by its rarity [8,23,24].
PATHOLOGY
Hallmark features — MSA is a synucleinopathy resulting in neuronal loss and atrophy in basal ganglia, brainstem nuclei, cerebellum, and corticospinal tracts. Cytoplasmic aggregates of alpha-synuclein in oligodendrocytes, referred to as glial cytoplasmic inclusions, are the pathologic hallmark. The involvement of glial cells distinguishes MSA from other synucleinopathies such as Parkinson disease (PD), in which alpha-synuclein aggregates (Lewy bodies) are present in neurons. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Pathology'.)
Alpha-synuclein immunostaining is a sensitive marker of inclusion pathology in MSA [8,25]. In addition to hyperphosphorylated alpha-synuclein, the glial cytoplasmic inclusions also contain tau, ubiquitin, leucine-rich repeat serine/threonine-protein kinase 2, and many other proteins [26-30]. Neuronal inclusions of various types, including Lewy body-like inclusions, are also present in the majority of patients [31,32].
The fibrillary structure of alpha-synuclein aggregates in MSA is distinct from that of other synucleinopathies, which may explain cell and region-specific vulnerabilities as well as differences in phenotype [33-36]. The secondary beta-sheet structure of folded alpha-synuclein filaments is distinct in MSA compared with fibrils found in Lewy bodies. Content of the beta-sheet structure in glial cytoplasmic inclusions is also lower than what is measured in Lewy bodies [37].
Neuropathologic distribution — The clinical presentation of MSA is largely determined by the pathologic distribution of glial cytoplasmic inclusions, along with the degree of neuronal loss within specific regions of the neuraxis. Neuronal cell loss correlates with the pathologic burden of glial cytoplasmic inclusions and disease duration [38]. Typical sites of pathologic involvement in MSA include the putamen, caudate nucleus, substantia nigra, locus ceruleus, pontine nuclei, inferior olivary nucleus, Purkinje cell layer of the cerebellum, and intermediolateral cell columns [39].
The pattern and degree of neuropathologic changes show some correlation with clinical subtype. Early changes in patients with predominant parkinsonism (MSA-P) are in the caudate, putamen, globus pallidus, and substantia nigra, whereas patients with predominant cerebellar ataxia (MSA-C) show more prominent cell loss in the cerebellum, pons, inferior olives, substantia nigra, and cerebral hemispheres [40,41]. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Motor involvement'.)
PATHOGENESIS — The cause of MSA is unknown [42]. However, the presence of alpha-synuclein messenger RNA (mRNA [ribonucleic acid]) in oligodendrocytes as well as glial inclusions and myelin disruption in the central nervous system suggest that MSA is a primary disorder of the glia [42-44].
Mechanisms — The mechanisms by which alpha-synuclein aggregates participate in the neurodegenerative cascade are under investigation.
One postulated mechanism involves prion-like spreading of aberrant alpha-synuclein from neurons to glia in MSA through functionally connected networks, thereby leading to glial and myelin dysfunction and an inflammatory cascade that promotes secondary neurodegeneration [45]. There have been a number of experimental studies demonstrating that abnormal alpha-synuclein aggregates might be responsible for the progression of MSA [46,47]. However, this remains controversial and is still an area of investigation [44,48].
Even before inclusions appear, oligodendrocytes undergo significant morphologic and biochemical changes, including cell enlargement, cytoplasmic clearing, and aggregation of tubulin polymerization-promoting phosphoprotein-25-alpha (p25α). p25a associates with myelin basic protein and moves from the nucleus and cell processes to the cytoplasm in oligodendrocytes prior to aggregation of alpha-synuclein [49,50].
Myelin degeneration is characteristic of MSA. A small case-control study found a significantly greater degree of white matter hyperintensities on magnetic resonance imaging (MRI) scans from patients with MSA compared with scans from patients with Parkinson disease (PD) and healthy controls [51]. This finding could be related to the dysfunction and loss of myelin or to cerebral hypoperfusion from orthostatic blood pressure fluctuations in MSA.
Neuroinflammation may also contribute to neurodegeneration in MSA. Increased numbers of activated microglia and astrocytes have been observed in autopsy specimens of patients with MSA, including microglia expressing nucleotide-binding domain, leucine-rich repeats-containing family, pyrin domain-containing-3 (NLRP3) inflammasome-related proteins in the putamen [52]. Further studies suggest that the inflammatory cascade may be propagated by interaction between alpha-synuclein and the NLRP3 inflammasome, leading to caspase 1 activation [53,54].
Clinical correlations — MSA by definition involves degeneration of multiple systems, which contribute to the varying clinical phenotypes of the disease. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Clinical features'.)
●Autonomic dysfunction – Autonomic dysfunction in MSA is secondary to loss of cells in the intermediolateral cell columns [55,56] and loss of catecholaminergic neurons of the C1 area of the ventrolateral medulla (VLM) [57]. This is manifested by severe variability in blood pressure and heart rate, orthostatic hypotension, syncope, and postprandial hypotension. Arginine-vasopressin release from magnocellular hypothalamic neurons is impaired; this may be mediated by loss of A1 neurons in the caudal VLM.
The peripheral autonomic system appears to be spared in MSA [58]. Some persistence of autonomic tone may be responsible for the frequently observed supine hypertension in MSA. By contrast, dysautonomia in PD is caused by peripheral nervous system dysfunction, particularly myocardial sympathetic denervation [59].
Mechanisms leading to urinary dysfunction include detrusor hyperreflexia from loss of inhibitory input to the pontine micturition center, loss of corticotropin-releasing factor neurons in the pontine micturition area [57], and bladder atonia primarily from severe damage to Onuf's nucleus in the sacral spinal cord. Damage to Onuf's nucleus is also the most likely cause of erectile dysfunction in males.
●Parkinsonism – Motor abnormalities seen in MSA with predominant parkinsonism (MSA-P) are due primarily to neuronal loss and gliosis in the substantia nigra, putamen, caudate, and globus pallidus [4]. One of the features that distinguishes MSA and other atypical parkinsonian syndromes (ie, Parkinson-plus syndromes) from idiopathic PD is the lack of dramatic and sustained response to levodopa, although in early MSA such a response may be seen temporarily. The extent of putaminal involvement may determine the poor response to levodopa [38].
●Cerebellar dysfunction – The cerebellar ataxia and pyramidal signs that characterize the MSA are secondary to degeneration of the cerebellar Purkinje cells, middle cerebellar peduncles, inferior olivary nuclei, basis pontis, and pontine nuclei. However, a majority of patients with predominant cerebellar ataxia (MSA-C) probably have subclinical loss of nigral neurons based upon findings from 123I-FP-CIT single-photon emission computed tomography (SPECT) imaging [60].
●Disordered sleep and breathing – Loss of cholinergic mesopontine neurons, combined with loss of locus ceruleus neurons and preservation of rostral raphe neurons, may contribute to rapid eye movement (REM) sleep abnormalities often seen in MSA [57].
Respiratory abnormalities may reflect loss of cholinergic neurons in the arcuate nucleus of the ventral medulla [57]. Respiratory stridor, abnormal nocturnal ventilation, and pseudobulbar features are possibly secondary to brainstem pathology, and may involve the nucleus ambiguus [8].
GENETICS — The role of genetics in the pathogenesis of MSA is undefined, and the vast majority of cases appear to be sporadic. One report found that variants in the coenzyme Q2, polyprenyltransferase (COQ2) gene were associated with familial MSA in two Japanese families [61]. Other reports have described familial patterns of MSA but have not identified a causative genetic variant [62-64].
Genetic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and the glucocerebrosidase (GBA1) gene, both common genetic forms of Parkinson disease, can present as MSA clinically as well as neuropathologically [65-67]. Another study identified a coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) pathogenic variant in a patient with MSA [68]. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Monogenic forms of PD'.)
Major risk alleles have not yet been identified, or studies have been conflicting. A genome-wide association study from Europe and North America that compared 918 patients with MSA and 3864 controls found no significant risk loci and, in particular, did not find an association of MSA with genetic variation in COQ2 or synuclein alpha (SNCA) [69], which had been reported in earlier studies [70-72]. Rather, the microtubule-associated protein tau (MAPT) was the only gene that appeared to be associated with MSA, and two other studies suggest that MAPT haplotypes H1x and H1 may be associated with an increased risk of MSA [73,74]. The role of tau isoforms in MSA is currently unknown.
SUMMARY
●Nomenclature – Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder of the basal ganglia, brainstem, cerebellum, and spinal cord that manifests with various combinations of autonomic dysfunction, parkinsonism, ataxia, and corticospinal degeneration.
MSA is a unifying term that brings together syndromes that used to be referred to as olivopontocerebellar atrophy (OPCA), striatonigral degeneration, and Shy-Drager syndrome. (See 'History and nomenclature' above.)
●Epidemiology – The estimated annual incidence of MSA in the population >50 years old is approximately 3 per 100,000 person-years. The mean age of onset ranges from 54 to 60 years. There appears to be no racial or sex predilection. (See 'Epidemiology' above.)
●Pathology – Cytoplasmic aggregates of alpha-synuclein in oligodendrocytes, referred to as glial cytoplasmic inclusions, are the pathologic hallmark of MSA. The inclusions also contain tau and ubiquitin. (See 'Hallmark features' above.)
Typical sites of pathologic involvement include the putamen, caudate nucleus, substantia nigra, locus ceruleus, pontine nuclei, inferior olivary nucleus, Purkinje cell layer of the cerebellum, and intermediolateral cell columns. (See 'Neuropathologic distribution' above.)
●Pathogenesis – The cause of MSA is unknown, but most evidence points to the disease being a primary disorder of the glia. One postulated mechanism involves prion-like spreading of aberrant alpha-synuclein through functionally connected networks. (See 'Pathogenesis' above.)
●Genetics – The genetic basis of MSA is not well understood, and the vast majority of cases appear to be sporadic. (See 'Genetics' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
