Multiple System Atrophy Treatment & Management
- Author: André Diedrich, MD, PhD; Chief Editor: Selim R Benbadis, MD more...
Approach Considerations
The cause of multiple system atrophy (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.
Nonpharmacologic treatment
- Constipation - A high-fiber diet, bulk laxative, lactulose, and suppositories can prevent constipation
- Stridor - Speech therapy is often useful to improve swallowing and communication
- Deconditioning - Physical therapy and an aquatic exercise program (hypotension does not occur while patients are in water) prevent physical deconditioning of the patient unless the movement disorder aspect of the illness so impairs balance that this is not advisable
- Urinary incontinence - Intermittent self catheterization or suprapubic or urethral catheterization can improve symptoms of urinary incontinence
- Falls - As the disease progresses, the risk of falls increases; proper gait instruction and precautions are critical to prevent falls and resultant injury
Pharmacologic treatment
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. (See Table 9.)
Surgical care
An atrial pacemaker may be used in patients with profound bradycardia in addition to orthostatic hypotension as a means of preventing the hypotension. However, this treatment is rarely undertaken and is rarely helpful.
Consider tracheostomy with the utmost care for intermittent respiratory stridor. Cricopharyngeal myotomy or gastrostomy has been used in patients with severe dysphagia, but its value is uncertain.
Consultations
Physical therapists, occupational therapists, speech therapists, and social workers can offer considerable practical help.
Diet
An essentially normal diet is recommended, with the following guidelines:
- Increased salt and fluid intake maintains plasma volume
- Small, frequent meals may help patients for whom postprandial hypotension is a significant problem
- A high-fiber diet, bulk laxatives, and suppositories prevent constipation
Activity
Exercise of muscles of the lower extremities and abdomen, water aerobics at hip level (not swimming, as it causes polyuria), and postural training, in combination with drug therapy, are useful.
Inpatient evaluation and tailoring of therapy are often important. However, if patients are restricted to bedrest, their functional mobility can decrease rapidly. Therefore, initiate physical therapy if the patient must remain in the hospital for longer than 2 days.
Nonpharmacologic Treatment of Hypotension and Hypertension
Orthostatic hypotension
The earliest symptom that brings patients to medical attention usually is orthostatic hypotension. Orthostatic hypotension leads to curtailing of physical activity, with all of the problems of deconditioning that consequently occur. Without an adequate upright BP, keeping patients active and on an exercise regimen is extremely difficult; therefore, management of orthostatic hypotension is one of the major tasks in the treatment of patients with MSA.
Mechanical maneuvers, such as leg-crossing, squatting, abdominal compression, bending forward, and placing 1 foot on a chair, can be effective in preventing episodes of orthostatic hypotension. Wearing an external support garment that comes to the waist improves venous return and preload to the heart during standing but loses effectiveness if the patient also wears it while supine. Increased salt and fluid intake and tilted sleeping with the head elevated increase the circulatory plasma volume.
Postprandial hypotension
Small, frequent meals attenuate BP drop after eating. Intake of water half an hour before meals or drinking coffee can counteract postprandial hypotension.
Supine hypertension
The management of patients with orthostatic hypotension and supine hypertension can be challenging, but adequate BP control is often achieved with the following treatment strategy:
- Use of over-the-counter medication with pressor effects
- Avoidance of fluid intake at bedtime
- Not using elastic stockings when supine
- Not using pressor agents before bedtime
- Raising the head of the bed 6-9 inches
- Resting on a semirecumbent chair with feet on the floor during the day
- Snacking before bedtime
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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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