Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology (original) (raw)
Practice Essentials
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders.
Signs and symptoms
Usually autonomic and/or urinary dysfunction develops first. The earliest symptom that brings patients to medical attention typically is orthostatic hypotension.
Other symptoms of MSA are based on mixed dysfunction. When the disorder results in nonautonomic features, imbalance caused by cerebellar or extrapyramidal abnormalities is the most common feature.
Diagnosis
MSA is a difficult diagnosis, especially early in the clinical course, and the initial physician often misdiagnoses the condition. The most common initial diagnosis is idiopathic Parkinson disease. [1]
The diagnosis of MSA is based mainly on clinical features.
Management
The cause of MSA remains unknown, and no current therapy can reverse or halt progression of the disease. The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat.
Drug therapy is directed mainly toward alleviation of symptoms of the movement disorder and orthostatic hypotension. Urinary incontinence, constipation, erectile dysfunction, and supine hypertension can also be addressed through pharmacologic therapy.
Background
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. Neuropathological hallmarks of MSA are cell loss in the striatonigral and olivopontocerebellar structures of the brain and spinal cord accompanied by profuse, distinctive glia cytoplasmic inclusions (GCIs) formed by fibrillized alpha-synuclein proteins (defined as primary alpha-synucleinopathy). (See Etiology and Pathophysiology, History and Physical Examination, and Workup.) [2]
A consensus statement by the American Autonomic Society and American Academy of Neurology in 2007 [3] categorized MSA in MSA-P with predominant parkinsonism and MSA-P with dominant cerebellar features (MSA-C). (See Categories of MSA below.)
The concept of MSA as a unitary diagnosis encompassing several clinical syndromes has a long history. The first cases of MSA were presented as olivopontocerebellar atrophy (OPCA) about a century ago. The Shy-Drager syndrome with features of parkinsonism and autonomic failure with OH was described in 1960. The term MSA was introduced to unify different forms of MSA in 1996. The discovery of GCIs and alpha-synuclein immunostaining as a sensitive marker of MSA were major milestones in the definition of MSA as a clinicopathologic entity. (See Table 1, below). [4]
Table 1. Historical Milestones in the Definition of Terms for MSA (Open Table in a new window)
| Term | Period | Authors | Comments |
|---|---|---|---|
| Olivopontocerebellar atrophy (OPCA) | 1900 | Dejerine and Thomas | Introduction of the term olivopontocerebellar atrophy |
| Orthostatic hypotension (OH) | 1925 | Bradbury and Eggleston | Introduction of autonomic failure as a clinical syndrome |
| Shy-Drager syndrome (SDS) | 1960 | Shy and Drager | Origin of this term as a neuropathologic entity with parkinsonism and autonomic failure with OH |
| Striatonigral degeneration (SND) | 1960 | Van der Eecken et al | Description of SND |
| Multiple system atrophy (MSA) | 1969 | Graham and Oppenheimer | Introduction of the term MSA, which represents SDS, SND, and OPCA as 1 entity |
| Glial cytoplasmic inclusions (GCIs) | 1989 | Papp et al, Matsuo et al | Discovery of GCIs as hallmark of MSA |
| Alpha-synuclein inclusion | 1998 | Spillantini et al, Wakabayashi et al | Alpha-synuclein immunostaining as a sensitive marker of MSA |
| MSA classification | 1996-1999 | Consensus Committee | Classification of MSA based on clinical domains and features and neuropathology |
| Unified MSA Rating Scale (UMSARS) | 2003 | European MSA Study Group | Unified MSA Rating Scale as a standard to define MSA symptoms [5, 6] |
| Second consensus for MSA | 2007 | Consensus Committee | New definition of MSA with simplified criteria |
A consensus conference in 2007 [7] simplified the older definition of MSA—as determined by the Consensus Committee representing the American Autonomic Society and the American Academy of Neurology in 1996 and 1998 [3] —and incorporated current knowledge for a better assessment of the disease. [8]
Categories of MSA
The 2 categories of MSA are as follows:
- MSA with predominant parkinsonism (MSA-P) - Extrapyramidal features predominate; the term striatonigral degeneration, parkinsonian variant is sometimes used
- MSA with cerebellar features (MSA-C) - Cerebellar ataxia predominates; it is sometimes termed sporadic olivopontocerebellar atrophy
The designation of MSA-P or MSA-C depends on the dominant feature at the time of evaluation, which can change with time.
Shy-Drager syndrome
When autonomic failure predominates, MSA was sometimes termed Shy-Drager syndrome (not defined in the present consensus anymore).
Characteristics of MSA
Features indicating the presence of MSA (tables 2a and 2b) or of another disorder (Table 3) are described below. (Corticospinal tract dysfunction with extensor plantar response with hyperreflexia [pyramidal sign] is not used to categorize MSA.) (See DDx.)
Table 2a. Main Features for the Diagnosis of MSA (Open Table in a new window)
| Clinical Domain | Feature | Comment |
|---|---|---|
| Autonomicdysfunction | Severe orthostatic hypotension (OH) Asymptomatic Symptomatic | OH is defined as blood pressure fall by at least 30mm Hg systolic and 15mm Hg diastolic within 3 minutes of standing from a previous 3-minute interval in the recumbent position.** |
| Urogenital dysfunction | Urinary incontinence (UI) or incomplete bladder emptying | UI is defined as persistent, involuntary, partial or total bladder emptying.ED usually occurs before symptomatic OH.*** |
| Erectile dysfunction (ED) in men | ||
| Parkinsonian features(87% incidence *) | Bradykinesia (BK) | BK is slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions.PI not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction. |
| Rigidity | ||
| Postural instability (PI) | ||
| Tremor - Postural, resting, or both | ||
| Cerebellar dysfunction(54% incidence *) | Gait ataxia (GA) | GA is a wide-based stance with steps of irregular length and direction.Sustained gaze-evoked nystagmus |
| Ataxic dysarthria | ||
| Limb ataxia | ||
| Oculomotor dysfunction | ||
| Coritcospinal tract dysfunction | Extensor plantar response with hyperreflexia | Babinsky sign, Pyramidal sign |
| *Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al [3] ).**OH caused by drugs, food, temperature, deconditioning, or diabetes are excluded.***ED does not count in the definition of onset of disease, because it is a general feature in older people. |
Table 2b. Additional Features for the Diagnosis of Possible MSA* (Open Table in a new window)
| Category | Additional Features |
|---|---|
| PossibleMSA-PPossibleMSA-C | Babinski sign with hyperreflexia Stridor |
| PossibleMSA-P | Rapidly progressive parkinsonism Poor response to levodopa Postural instability within 3 years of motor onset Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Dysphagia within 5 years of motor onset Atrophy on magnetic resonance imaging (MRI) of putamen, middle cerebellar peduncle, pons, or cerebellum Hypometabolism on 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scanning in putamen, brainstem, or cerebellum |
| PossibleMSA-C | Parkinsonism (bradykinesia and rigidity) Atrophy on MRI of the putamen, middle cerebellar peduncle, or pons Hypometabolism on FDG-PET in the putamen Presynaptic striatonigral dopaminergic denervation on single-photon emission computed tomography (SPECT) or PET scanning |
| *Modified from second consensus [7] |
Table 3. Characteristics That Do Not Support the Diagnosis of MSA (Open Table in a new window)
| Procedure | Nonsupporting Features |
|---|---|
| History taking | Symptomatic onset at < 30 years Onset after age 75 years Family history of ataxia or parkinsonism Systemic diseases or other identifiable causes for features listed in Table 2a Hallucinations unrelated to medication Dementia |
| Physical examination | Classic parkinsonian pill-rolling rest tremor Clinically significant neuropathy Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence of focal cortical dysfunction, such as aphasia, alien limb syndrome, and parietal dysfunction |
| Laboratory study | Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2a White matter lesions suggesting multiple sclerosis |
Levels of certainty of MSA
MSA can be ascertained as possible, probable, or definite MSA (see Table 4, below), based on autonomic and urogenital features, on the presence of parkinsonism, and on cerebellar dysfunction, as well as on additional features (see tables 2a and 2b, above).
Only pathologic findings of high density of alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) and degenerative changes in the striatonigral or olivopontocerebellar pathways can definitively confirm the diagnosis of MSA. (See Workup.)
Table 4. Diagnostic Categories of MSA (Open Table in a new window)
| Category | Definition |
|---|---|
| Possible MSA | A sporadic, progressive, adult (>30y) with onset disease* characterized by the following: Parkinsonism or cerebellar syndrome At least 1 feature of autonomic or urogenital dysfunction At least 1 of the additional features from Table 2b |
| Probable MSA | A sporadic, progressive, adult (>30y) with onset disease* characterized by the following: Autonomic failure involving urinary dysfunction Poorly levodopa-responsive parkinsonism or cerebellar dysfunction |
| Definitive MSA | A sporadic, progressive, adult (>30y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in striatonigral and olivopontocerebellar pathways |
| *Disease onset is defined as the initial presentation of any parkinsonian or cerebellar motor problems or autonomic features (except erectile dysfunction). |
Red flags supporting the diagnosis of MSA include the following:
- Orofacial dystonia
- Disproportionate antecollis
- Severe anterior flexion of the spine (camptocormia)
- Severe lateral flexion of the spine (Pisa syndrome)
- Contractures of hands and feet
- Inspiratory sighs
- Severe dysphonia
- Severe dysarthria
- New or increased snoring
- Cold hands and feet
- Pathologic laughter or crying
- Jerky myoclonic postural/action tremor
Patient education
A variety of resources are available for patient education. These include the Web sites of the Multiple System Atrophy Coalitions, Autonomic Disorder Consortium of the Clinical Rare Diseases Research Network, and Vanderbilt Autonomic Dysfunction Center.
Etiology and Pathophysiology
MSA is characterized by progressive loss of neuronal and oligodendroglial cells in numerous sites in the central nervous system (CNS). The cause of MSA remains unclear, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically. [9] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak.
There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance [10] and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported. [11] Single nucleotide polymorphisms (SNPs) at the SNCA locus coding for alpha-synuclide have been identified. G51D mutation in the SNCA locus has been described, but a connection between SCNA locus and MSA disease could not be confirmed. Associations with COQ2 and C9orf72 have been reported. [12, 13]
Researchers initially assumed that gray-matter damage caused MSA. However, the discovery of oligodendroglial glial cytoplasmic inclusions (GCIs) (see Table 8) indicated that damage primarily affects the white matter. [14] The chronic alterations in glial cells may impair trophic function between oligodendrocytes and axons and cause secondary neuronal damage. Whether the inclusions represent primary lesions or nonspecific secondary markers of cellular injury remains unknown. In addition to the GCIs, extensive myelin degeneration occurs in the brain. Changes in myelin may play an important role in the pathogenesis of MSA. The clinical symptoms of MSA correlate with cell loss in different CNS sites. (See Table 5, below.)
Table 5. Clinicopathologic Correlations (Open Table in a new window)
| Clinical Symptom | Pathologic Findings and Location of Damage or Cell Loss |
|---|---|
| Orthostatic hypotension | Primary preganglionic damage of intermediolateral cell columns |
| Urinary incontinence (not retention) | Preganglionic cell loss in spinal cord (intermediolateral cell columns), related to detrusor hyperreflexia caused mainly by loss of inhibitory input to pontine micturition center (rather than to external urethral sphincter denervation alone) |
| Urinary retention caused by detrusor atonia | Sacral intermediolateral cell columns |
| Cerebellar ataxia | Cell loss in inferior olives, pontine nuclei, and cerebellar cortex |
| Pyramidal signs | Pyramidal tract demyelination |
| Extensor plantar response | Pyramidal tract lesion |
| Hyperreflexia | Pyramidal tract lesion |
| Motor abnormalities | GCIs in cortical motor areas or basal ganglia |
| Akinesia | Putamen, globus pallidus |
| Rigidity | Putaminal (not nigral) damage |
| Limb and gait ataxia | Inferior olives, basis pontis |
| Decreased or absent levodopa responsiveness | Striatal cell loss, loss of D1 and D2 receptors in striatum or impaired functional coupling of D1 and D2 receptors |
| Nystagmus | Inferior olives, pontine nuclei |
| Dysarthria | Pontine nuclei |
| Laryngeal stridor | Severe cell loss in nucleus ambiguus or biochemical defect causing atrophy of posterior cricoarytenoid muscles |
| Excessive daytime sleepiness | Loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons [15] |
| Adapted from Wenning et al and other sources. |
Epidemiology
Occurrence in the United States
The prevalence of MSA is reported to be between 3.4-4.9 cases per 100,000 population. The estimated mean incidence is 0.6-0.7 cases per 100,000 person-years. MSA meets orphan disease status. [16, 17]
Many patients do not receive the correct diagnosis during their lifetime because of the difficulty in differentiating MSA from other disorders (eg, Parkinson disease, pure autonomic failure [PAF], other rare movement disorders). About 29-33% of patients with isolated late-onset cerebellar ataxia and 8-10% of patients with parkinsonism will develop MSA. Therefore, a higher prevalence than that estimated can be assumed.
International occurrence
In the European Union (EU), the prevalence rates show 4-5 cases per 100,000 persons. The incidence rate is about 0.6 cases per 100,000 persons per year. [18]
In the United Kingdom, the crude prevalence of MSA, including all probable and possible cases, is 3.3 per 100,000 population. [19]
In Iceland, the incidence is 0.6 per 100,000 and prevalence is 3.1 per 100,000. [20]
In Japan, the prevalence is 13.1 per 100,000 individuals. The mean annual incidence is 0.68. [21]
Race-, sex-, and age-related demographics
MSA has been encountered in Caucasian, African, and Asian populations. In Western countries, MSA-P predominates, occurring in 66-82% of patients. In Eastern countries (e.g., Japan), MSA-C is common, occurring in 67% of patients.
The disease more often affects men than women. The female-to-male ratio is around 1:2. (A ratio of 1:3-9 has also been reported.) However, the early and easy diagnosis of impotence may have led to the male statistical predominance of MSA. The mean age at onset in MSA is 52.5-55 years. The disease progresses over intervals of 1-18 years.
Prognosis
Patients with MSA have a poor prognosis. The disease progresses rapidly. Median survivals of 6.2-9.5 years from the onset of first symptoms have been reported since the late 20th century. No current therapeutic modality reverses or halts the progress of this disease. MSA-P and MSA-C have the same survival times, but MSA-P shows more rapid dysfunctional progression.
An older age at onset has been associated with shorter duration of survival in MSA. The overall striatonigral cell loss is correlated with the severity of disease at the time of death.
Bronchopneumonia (48%) and sudden death (21%) are common terminal conditions in MSA. Urinary dysfunction in MSA often leads to lower urinary tract infections (UTIs); more than 50% of patients with MSA suffer from recurrent lower UTIs and a significant number die of related complications. [22]
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Author
André Diedrich, MD, PhD Research Professor of Medicine and Biomedical Engineering, Autonomic Dysfunction Center, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center
André Diedrich, MD, PhD is a member of the following medical societies: American Autonomic Society
Disclosure: Nothing to disclose.
Coauthor(s)
David Robertson, MD Director, Clinical and Translational Research Center, Vanderbilt Institute for Clinical and Translational Research, Principal Investigator, Autonomic Rare Disease Clinical Research Consortium, Elton Yates Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University School of Medicine
David Robertson, MD is a member of the following medical societies: American Heart Association, Association of American Physicians
Disclosure: Nothing to disclose.
Chief Editor
Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity, Catalyst, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK Life Science Science, Sunovion, Takeda, UCB
Serve(d) as a speaker or a member of a speakers bureau for: Catalyst, Jazz, LivaNova, Neurelis, SK Life Science, Stratus, UCB
Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard.
Acknowledgements
Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.
Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment