Multiple System Atrophy Clinical Presentation
- Author: André Diedrich, MD, PhD; Chief Editor: Selim R Benbadis, MD more...
History and Physical Examination
Most patients with multiple system atrophy (MSA) develop the disease when they are older than 40 years (average 52-55y), and they experience fast progression. Usually autonomic and/or urinary dysfunction develops first. Patients with MSA may have parkinsonian symptoms with poor or nonsustained response to levodopa therapy. Only 30% of MSA-P patients have an initial transient improvement. About 90% of patients are nonresponsive to long-term levodopa therapy.
Typically, 60% of patients experience objective decline in motor function within 1 year. Motor impairment can be caused by cerebellar dysfunction. Corticospinal tract dysfunction also can occur but is not often a major symptomatic feature of MSA. Table 2a provides an overview of the clinical domains and their main features. More details are described in subsequent sections.[13]
Autonomic and/or urinary dysfunction
Autonomic symptoms are the initial feature in 41-74% of patients with MSA; these symptoms ultimately develop in 97% of patients. Genitourinary dysfunction is the most frequent initial complaint in women, and erectile dysfunction is the most frequent initial complaint in men.
Severe orthostatic hypotension
Severe orthostatic hypotension is defined as a reduction in systolic blood pressure (BP) of at least 30mm Hg or in diastolic BP of at least 15mm Hg, within 3 minutes of standing from a previous 3-minute interval in the recumbent position. This form of hypotension is common in MSA, being present in at least 68% of patients. Most patients do not respond with an adequate heart rate increase. The definition of severe orthostatic BP fall as a diagnostic criterion for MSA is stricter than the definition of orthostatic hypotension as a physical finding as defined by the American Autonomic Society.[14]
Symptoms associated with orthostatic hypotension include the following:
- Light-headedness
- Dizziness
- Dimming of vision
- Head, neck, or shoulder pain
- Altered mentation
- Weakness - Especially of the legs
- Fatigue
- Yawning
- Slurred speech
- Syncope
Some patients have fewer orthostatic symptoms. In 51% of patients with MSA, syncope is reported at least once. In 18% of patients with severe hypotension, more than 1 syncopal episode is documented. Because of dysautonomia-mediated baroreflex impairment and consequent debuffering, patients respond in an exaggerated fashion to drugs that raise or lower their BP.
Orthostatic hypotension must be distinguished from postural tachycardia syndrome, which is defined as an increase in heart rate of greater than 30 beats per minute (bpm) and maintained BP (absence of orthostatic hypotension).
Postprandial hypotension
Patients are also susceptible to postprandial hypotension. Altered venous capacitance and baroreflex dysfunction have been reported as a cause.[15]
Supine hypertension
Approximately 60% of patients with MSA have orthostatic hypotension and supine hypertension. The supine hypertension is sometimes severe (>190/110mm Hg) and complicates the treatment of orthostatic hypotension.
Parkinsonism
Parkinsonism can be the initial feature in 46% of patients with MSA with predominant parkinsonism (MSA-P); it ultimately develops in 91% of these MSA-P patients. Although akinesia and rigidity predominate, tremor is present at rest in 29% of patients; however, a classic pill-rolling parkinsonian rest tremor is recorded in only 8-9%. Patients with MSA-P have a poor response to levodopa.
About 28-29% of patients have a good or even excellent levodopa response early in their disease. However, only 13% maintain this response. Patients with early onset (at < 49 y) MSA-P tend to have a good levodopa response.
Patients sometimes complain of stiffness, clumsiness, or a change in their handwriting at the onset of the disease.
Cerebellar dysfunction
Cerebellar symptoms or signs are the only initial feature in 5% of MSA patients. MSA with cerebellar features (MSA-C) most commonly causes gait and limb ataxia; tremor, pyramidal signs, and myoclonus are less common findings.
Additional symptoms
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.
If the cerebellar, extrapyramidal, and pyramidal systems are involved, the movement disorder is usually the most profound disability.
Vocal cord paralysis may lead to hoarseness and stridor. A neurogenic and obstructive mixed form of sleep apnea can occur.
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- Table 1. Historical Milestones in the Definition of Terms for MSA
- Table 2a. Main Features for the Diagnosis of MSA
- Table 2b. Additional Features for the Diagnosis of Possible MSA*
- Table 3. Characteristics That Do Not Support the Diagnosis of MSA
- Table 4. Diagnostic Categories of MSA
- Table 5. Clinicopathologic Correlations
- Table 6. Differential Diagnosis of MSA and Parkinson Disease[18]
- Table 7. Differential Diagnosis of MSA and PAF
- Table 8. Differences Between GCIs in MSA and Other Pathologic Inclusions and Structures
- Table 9. Drugs Used to Manage Orthostatic Hypotension in MSA
| 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[4, 5] |
| Second consensus for MSA | 2007 | Consensus Committee | New definition of MSA with simplified criteria |
| Clinical Domain | Feature | Comment |
| Autonomic dysfunction | Severe orthostatic hypotension (OH)
| 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 | ||
| *Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al[2] ). **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. | ||
| Category | Additional Features |
| Possible MSA-P Possible MSA-C |
|
| Possible MSA-P |
|
| Possible MSA-C |
|
| *Modified from second consensus[6] | |
| Procedure | Nonsupporting Features |
| History taking |
|
| Physical examination |
|
| Laboratory study |
|
| Category | Definition |
| Possible MSA | A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
|
| Probable MSA | A sporadic, progressive, adult (>30y) with onset disease* characterized by the following:
|
| 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). | |
| 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[11] |
| Adapted from Wenning et al and other sources. | |
| Characteristic | MSA | Parkinson Disease |
| Response to chronic levodopa therapy* | Poor or unsustained motor response because of loss of postsynaptic dopamine receptors Initial improvement in 30% of patients with MSA, but 90% were unresponsive over a longer time; 50% develop levodopa-induced dyskinesia of orofacial and neck muscles | Good response |
| Effects on striatonigral transmission | Presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum, as well as their striatal target cells, have reduced dopamine receptors | Presynaptic |
| Symmetry of movement disorder | Possibly asymmetrical | No data |
| Progression of symptoms | Rapid | Slow |
| Postural instability and falling** | Early Fast progression Worsen >20% of UPDRS scale** | Late Less progression (< 10%) |
| Progress of disability | Relatively fast disability; 30% decrease of activities of daily living in 1 year; 40% of patients in a wheelchair within 5 years (wheel chair sign) | Relatively slow disability |
| Abnormal speech | Severely affected speech in 30% of patients with MSA Dysarthrophonia and severe dysarthria are common | Less affected |
| Abnormal Respiration | Abnormal aspiration, inspiratory gasps, and stridor in 60% of patients with MSA Stridor caused by paralysis of vocal cord occurs especially at night but is also present during day | Less common |
| Lewy bodies (hyaline eosinophilic cytoplasmic neuronal inclusions) | Not present*** | Primarily in substantia nigra |
| Cytoplasmic inclusions (immunocytochemical reaction with antibodies to alpha synuclein) | Glial inclusions; argyrophilic cellular inclusions in oligodendrocytes | Absent |
| Thermoregulation, skin perfusion | Cold hands and decrease of warm-up after cold-pack stimulus | Normal |
| Caudate-putamen index of dopamine uptake (on positron emission tomography [PET] scanning) | Decreased in putamen and caudate | Decreased in putamen with smaller decrease in caudate |
| Growth hormone release with intravenous (IV) injection of clonidine | No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit) | Increase of growth hormone, intact function |
| * A positive response to levodopa is defined as a significant improvement of motor features during 3 months’ application of escalating doses of levodopa with a peripheral decarboxylase inhibitor.[6] ** Postural instability as defined by item 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor examination).[6] *** Pakiam et al reported that patients with diffuse Lewy-body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling some proposed criteria for the striatonigral form of MSA.[19] | ||
| Characteristic | MSA | Pure Autonomic Failure |
| CNS involvement | Multiple involvement | Unaffected |
| Site of lesion | Mainly preganglionic, central; degeneration of intermediolateral cell columns; ganglionic neurons relatively intact | Mainly postganglionic; loss of ganglionic neurons |
| Progression | Fast; median survival 6.5-9.5 years | Slow; some patients survive >10-30 years |
| Prognosis | Poor | Good |
| Extrapyramidal involvement | Common | Not present |
| Cerebellar involvement | Common | Not present |
| Gastrointestinal symptoms | Uncommon | Absent, except constipation |
| Plasma supine norepinephrine level | Normal | Reduced |
| Antidiuretic hormone (ADH) response to tilt | Impaired because of catecholaminergic denervation of hypothalamus (but normal ADH response to osmotic stimuli) | Maintained |
| Adrenocorticotropic hormone and beta-endorphin response to hypoglycemia | Impaired because of central cholinergic dysfunction or dysfunction of adrenergic input to paraventricular nucleus | Normal |
| Growth hormone release with clonidine IV injection | No release, dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit) | Increase of growth hormone; intact function |
| Substance P, catecholamine, 5-HT, and acetylcholine markers in cerebrospinal fluid | Decreased levels | No data |
| Lewy bodies | Mostly absent | Present in autonomic neurons |
| BP response to oral water intake | Increased | Increased but variable |
| BP response to ganglionic blockade | Profound decrease | Modest decrease |
| GCIs in MSA | Lewy Bodies in Parkinson Disease | Neurofibrillary Pathology in Alzheimer Disease | Glial Lesions in Corticobasal and Progressive Supranuclear Palsy | |
| Shape | Sickle shaped to flame shaped to ovoid, various neurofibrillary tangles | Target-shaped inclusions | Tangles | Tufted astrocytes, coiled bodies |
| Membrane | No limiting membrane; tubular profiles and electrodense granules | Present | Present | Present |
| Ultrastructure | Loosely aggregated filaments | No data | No data | Astrocytic plaques |
| Immunocytochemistry | Ubiquitin positive, alpha-B-crystallin (synuclein) positive, alpha- and beta-tubulin positive, tau-protein positive | Hyaline eosinophilic cytoplasmic neuronal inclusions, ubiquitin | No data | Absence of phosphorylated tau |
| Localization | In oligodendroglial cells and neurons | In neuronal cells and oligodendroglial cells | No data | No data |
| Class | Drug | Description or Mechanism |
| Corticosteroids | Fludrocortisone (Florinef) | Mineralocorticoid; sodium retention, primarily in extravascular compartment, causes tissue edema to venous capacitance bed in lower extremity. With this edema, venous bed accommodates decreased volume of blood in an upright posture (high doses, late effect); increases sensitivity to norepinephrine (even with small doses) |
| Sympathomimetic amines | Midodrine | Alpha1-adrenoreceptor agonist acts directly on vasculature, causes venous and arteriolar vasoconstriction |
| Droxidopa (investigational) | Droxidopa is a synthetic precursor of norepinephrine. It acts by conversion to norepinephrine in the body. | |
| Recombinant erythropoietin (EPO) | Epoetin alfa | Increases sensitivity to pressor effects of angiotensin II; increases plasma endothelin level; increases cytosolic free calcium in vascular smooth muscle; increases intravascular volume |
| NSAIDs | Indomethacin, ibuprofen | Inhibition of vasodilator prostaglandins proposed but not proven |
| Antihistamines | Diphenhydramine, cimetidine | Reduce vasodilatation caused by histamine release |
| Somatostatin analogs | Octreotide | Reduce splanchnic capacitance |
| Vasopressin agonists | Desmopressin (DDAVP) | Vasopressin analogs; no effect on V1 receptors, which are responsible for vasopressin-induced vasoconstriction; acts on V2 receptors on renal tubuli, which are responsible for antidiuretic effect; prevents nocturnal diuresis, raises BP in morning |
| Other sympathomimetics | Yohimbine | Alpha2-adrenoreceptor antagonist |
| Caffeine | Adenosine receptor antagonist |
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