Multiple system atrophy refers to a group of progressive neurodegenerative disorders, previously referred to as striatonigral degeneration,olivopontocerebellar atrophy and Shy-Drager syndrome. The latter was named after the two physicians who first described it in 1960: Dr. Milton Shy from the National Institutes of Health and Dr. Glenn Drager from Baylor College of Medicine. Currently MSA is divided into two categories: MSA-P, which suggests MSA with predominant parkinsonism and MSA-C, which refers to MSA with predominant cerebellar ataxia. When Shy-Drager syndrome was an entity, it associated with predominant autonomic disturbances, but it is now accepted that dysautonomia is part of both MSA-P and MSA-C and a separate category is not necessary. Usually, over time, people with MSA will develop both parkinsonism and cerebellar features, though the diagnosis of MSA is typically followed with the letter P or C to denote which features are most prominent. A probable diagnosis is made when patients exhibit autonomic failure with either parkinsonism or cerebellar ataxia. A definite diagnosis can only be made upon autopsy and if the typical alpha-synuclein-containing protein aggregates known as glial intracytoplasmic inclusion bodies are present. In North America, the parkinsonian subtype seems to predominate whereas in Japan, the cerebellar pattern is more common. Patients often exhibit pyramidal symptoms as part of the disease but cognitive problems are not a common feature. Mean age of onset is approximately 60 years of age with a prevalence of 2 to 5 per 100,000 people and an incidence as high as 3 per 100,000.
Symptoms and Signs of Dysautonomia (MSA-A)
Dysautonomia refers to a disturbance of the autonomic nervous system, the nerve pathways which regulate unconscious bodily functions including heart rate, blood pressure, digestion, salivation, perspiration, micturition (release of urine), and some sexual functions. Commonly, patients with dysautonomia experience symptoms of fainting or dizziness upon changing to a more upright position (such as from lying to sitting or sitting to standing up). The lightheadedness results from a drop in blood pressure that occurs upon rising, which in turn decreases the amount of blood returning to the brain. When a patient collapses to the floor, the amount of blood reaching the brain increases as the blood pressure rises, and the patient regains consciousness. Other typical symptoms of autonomic nervous system dysfunction are constipation, impotence in males, and loss of bladder or bowel control leading to incontinence or retention. Some patients experience abnormal sweating and develop bluish-purplish discoloration of skin known as the cold hand or cold foot sign. MSA patients also frequently snore, have longer than normal pauses in breathing during sleep (sleep apnea), and exhibit combative behavior while asleep, known as REM Behavioral Disorder (RBD).
Symptoms and Signs of Parkinsonism (MSA-P)
The parkinsonian features of MSA typically include a slowed and shuffling gait, difficulty with balance, stiffness (rigidity) of muscles, particularly those involving the neck, and slurred and low-volume speech. Neck and trunk muscle rigidity or weakness may result in abnormal postures such as forward bending of the neck (anterocollis) or a body tilt when sitting (Pisa sign). Tremor, if present, is usually mild. Patients also may develop hoarseness, difficulty breathing from vocal cord weakness, and frequent involuntary sighing.
MSA-P is more common in men than women, usually presenting in one's late 40's or early 50's. Initial symptoms of MSA overlap with those of Parkinson's disease, and many patients with MSA are first diagnosed with classic Parkinson's disease. Some patients initially respond to the same medications used for Parkinson's disease but unfortunately, the benefit is usually transient. The course of the MSA-P varies markedly from one individual to another; while some patients live for up to 20 years after the onset of symptoms, most patients reach severe disability, requiring assistance with walking and other activities of daily living within 5-8 years. It usually progresses much more rapidly than Parkinson's disease.
Symptoms and Signs of Cerebellar Dysfunction (MSA-C)
MSA-C is characterized by poor coordination and progressive loss of balance (ataxia). In addition, patients with MSA-C may have action tremor, which is different from the resting tremor seen in typical Parkinson's disease. This tremor is present during activities, such as reaching for objects or eating, and can be elicited on examination by the finger-to-nose maneuver. Other features include slurring of speech, difficulty with swallowing, and progressive weakness. Age at onset ranges from the early 20's to the 60's. The first symptom is usually mild incoordination in one's hands and legs, which eventually progresses to loss of balance requiring a walker or a wheelchair.
There is no diagnostic test for MSA, but a neurologist usually suspects the diagnosis based on a patient's physical examination and clinical course. Early in the disease, it can be challenging to differentiate MSA-P from Parkinson's disease. MSA-C may be confused with inherited forms of cerebellar ataxia if a careful family history is not elicited.
In MSA-P, brain MRI scans, may demonstrate abnormal signal in the putamen (a cluster of cells deep in the brain involved in regulating movement). In cases of MSA-C, MRI shows atrophy, or shrinkage of the cerebellum and brainstem. It may also show the "hot cross bun sign" which suggests degeneration of the ventral pontine fibers. Brain scans, however, cannot not always distinguish MSA from other neurodegenerative diseases. Also, because MSA is a rare condition, these characteristic changes are sometimes not recognized by radiologists; therefore, the scans should be examined by a neurologist experienced in the diagnosis of MSA.
Diagnosis of MSA may also be aided by testing the autonomic nervous system, for example, by measuring blood pressure and heart rate with the patient lying down compared with standing up. A drop in blood pressure while standing (orthostatic hypotension) is suggestive of autonomic dysfunction. A sleep study (polysomnogram) can document sleep apnea. Upon autopsy, characteristic patterns of degeneration may be seen but in all cases, the diagnosis of MSA cannot be confirmed unless and reveals the oligodendroglial, alpha-synuclein-containing protein aggregations known as glial cytoplasmic inclusion bodies are found.
Despite intensive research, the cause of MSA is still unknown. There is little evidence that MSA is a genetic disorder, as most with MSA have no family history of neurological disease. The pathological findings of MSA are distinct from Parkinson's disease; however, studies suggest that there may be an overlap between these two disorders. Like those with Parkinson's disease, patients with MSA accumulate the protein, alpha-synuclein, within specific brain cells. Why this protein is mishandled and how that results in nerve cell damage remains an area of intense interest among neuropathologists and other neuroscientists. Abnormalities with the SNCA (alpha synuclein gene) have been found to increase the risk of developing MSA. MSA-C has also been reported to be rarely caused by the gene for another disorder of coordination, namely spinocerebellar ataxia (SCA3).
In the early stages of MSA, levodopa and drugs that act directly on dopamine receptors (dopamine agonists) may lessen parkinsonian symptoms, such as slowness of movement. On average, however, these drugs are less effective in patients with MSA compared to those with Parkinson's disease (PD). Also, as in PD, many patients with MSA develop involuntary movements (dyskinesias), particularly involving their face, after prolonged levodopa use. Levodopa may also lower blood pressure, which is problematic for patients with autonomic dysfunction.
For patients with autonomic dysfunction, there are treatments that lessen the drop in blood pressure when upright. These treatments include increasing the amount of salt in the diet, fludrocortisone (a steroid hormone), midodrine and pyridostigmine (drugs that stimulate the autonomic nervous system), and the daytime use of support hose such as Jobst stockings to decrease pooling of blood in the legs. Because these methods can increase blood pressure to undesirably high levels when the patient is lying down, the head of the patient's bed should be elevated at least 30 degrees. Continuous Positive Airway Pressure (CPAP) breathing machines at night may be helpful for those patients with MSA who have documented sleep apnea. Increased urinary frequency due to an overactive bladder usually improves with solifenacin (VESIcare), tolterodine (Detrol) or similar medications. Sildenafil (Viagra) and related drugs may be effective for erectile dysfunction but can unmask dizziness (orthostatic hypotension) and should be used with caution. Urological consultation is recommended in most cases of MSA. Because of swallowing problems some patients require placement of a feeding tube (PEG) directly into the stomach in order to maintain adequate nutrition and prevent aspiration pneumonia.
Non-drug treatments for MSA include physical therapy and stretching exercises designed to maintain strength and flexibility. Devices which make ambulation safer, such as a walker, can also be helpful. At present, there are no therapies that can reverse or even retard the progression of MSA. Transgenic mouse models, albeit imperfect, have allowed us to explore more potential therapies and follow up with clinical trials; however, trials investigating minocycline, riluzole, rasagiline and other agents have not yet revealed any neuroprotective benefit. Furthermore, since MSA is rare, clinical drug trials are sometimes not available for affected patients. Nonetheless, there is reason for hope. Because the biology of MSA may be related to other neurodegenerative diseases, like Parkinson's disease, it is possible that therapies designed for other conditions will also prove helpful for patients with MSA.
©2011 Joseph Jankovic, M.D.
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