Multiple System Atrophy
MULTIPLE SYSTEM ATROPHY
Multiple system atrophy is a group of disorders that share common clinical features, which include Parkinsonism, problems with balance (ataxia), and dysfunction of the autonomic nervous system. It is a sporadic neurodegenerative disease of adult onset. Its cause remains unknown.
Parkinsonism is a part of the constellation of symptoms, hence multiple system atrophy also falls within the rubric of disorders called Parkinson-plus syndromes. In addition to multiple system atrophy, Parkinson-plus syndromes include progressive supranuclear palsy and corticobasal ganglionic degeneration. Some also consider Lewy-body disease to be one these syndromes. The Parkinson-plus syndromes are distinct from idiopathic Parkinson's disease because of certain aspects of clinical presentations, but more importantly, are differentiated by clinical response to treatment with L-dopa and related drugs, and neuropathology. In early stages, Parkinson-plus syndromes can be difficult to distinguish from idiopathic Parkinson's disease. However, patients with idiopathic Parkinson's disease have significant improvement of symptoms with dopaminergic drugs, while patients with Parkinson-plus syndrome have, at best, a modest response, so that a diagnosis of Parkinson-plus syndrome is often first considered only when patients show an atypically modest response to treatment. Within the context of Parkinson-plus syndromes, multiple system atrophy is a distinct entity because of its clinical features and neuropathological expression.
In 1900, Déjérine and Thomas coined the term olivopontocerebellar atrophy to describe a disorder in which the predominant clinical feature was ataxia, but also included parkinsonism and autonomic dysfunction. In 1960, Shy and Drager described patients in whom there was predominant autonomic dysfunction manifested primarily by a sudden fall in the blood pressure on standing (orthostatic hypotension). These patients also had parkinsonism, and to a lesser degree, ataxia. The disorder has been called Shy-Drager Syndrome. In the 1960s, Adams and his colleagues described a group of patients with predominant parkinsonism who also had autonomic failure and, to a lesser degree, ataxia. They termed this disorder striatonigral degeneration.
The neuropathological description of these disorders shows changes in various structures, predominantly the basal ganglia, cerebellum, and certain brainstem nuclei. Because of the common features, both clinically and neuropathologically, Graham and Oppenheimer suggested that these three sporadic, adult-onset, neurodegenerative disorders be considered as one diagnostic entity, namely multiple system atrophy. This grouping of patients with sporadic olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager Syndrome as one entity was further strengthened by the observation that all these disorders had a common neuropathological feature, namely intracytoplasmic inclusion bodies (a collection of abnormal molecules) in the oligodendrocytes, which are cells that provide structural and functional support for the brain cells (neurons).
Clinical features
Four features are present in idiopathic Parkinson's disease: slowing of movement (bradykinesia), tremor, muscle rigidity, and a tendency to fall. The four together mean that Parkinson's disease can be diagnosed. When three or fewer are present, the combination is referred to as parkinsonism.
Parkinsonism occurs, to some degree, in the majority of patients with multiple system atrophy. This is more prominent in striatonigral degeneration type of multiple system atrophy. Slowing of movement (bradykinesia) and rigidity are more common, while tremor, which is more common in idiopathic Parkinson's disease, is less prominent in multiple system atrophy. Furthermore, like idiopathic Parkinson's disease, these patients also display gait disturbance, which is independent of ataxia. In contrast to idiopathic Parkinson's disease, the parkinsonian symptoms in these patients respond poorly to dopaminergic agents.
Ataxia
Ataxia of the limbs generally occurs first, predominantly in patients with olivopontocerebellar-type of multiple system atrophy. This leads to gait disturbance. Ataxia in these patients is of cerebellar origin and this can progress to other cerebellar signs, which include dysarthria (speech impairment), and myoclonus (jerking movement of muscles). Abnormalities of eye movements of the cerebellar origin also occur, such as nystagmus (involuntary movements of the eyeball). Examination of the eye movements is important in terms of diagnosis because supranuclear vertical gaze abnormalities, that is, inability to move eyes voluntarily, particularly downward, would be consistent with a diagnosis of progressive supranuclear palsy rather than multiple system atrophy.
Autonomic dysfunction
Autonomic dysfunction occurs in a significant number of patients with multiple system atrophy and is more prominent in patients with Shy-Drager Syndrome. Clinical manifestations of autonomic dysfunction include orthostatic hypotension, gastrointestinal disturbance (i.e., constipation or fecal incontinence), urinary disturbance including urinary retention, urinary incontinence, and impotence. In addition to this, there is impairment in sweating. Postural hypotension in which there is a drop in the systolic blood pressure of 20 mm or more upon standing can cause significant disability in these patients. Some of the symptoms include lightheadedness, although loss of consciousness can also occur leading to morbidity in these patients. In terms of gastrointestinal symptoms, constipation is more common, however, dysphagia (inability to swallow) may become prominent as the disease progresses. While urinary incontinence and retention may occur, impotence is another significant autonomic dysfunction, particularly in men, which occurs in approximately 95 percent of patients at some point of the disease process.
Other general neurological findings in these patients may include upper motor neuron findings, including brisk deep tendon reflexes (such as knee jerk reflex) and extensor plantar responses (that is, up-going toe on stroking the sole of the foot. Normal response is for the toe to go down or remain in neutral position). These findings may occur in up to two-thirds of patients with multiple system atrophy, but are not a common feature of idiopathic Parkinson's disease.
Cognitive function
The majority of patients with multiple system atrophy displays a mild form of cognitive impairment reflecting frontal-subcortical system dysfunction. This is predominantly manifested by disturbances in attention, mild problems with memory, visuospatial dysfunction, and executive dysfunction.
Natural history
The age range for onset of multiple system atrophy is between 33.3 years to 75.6 years with a mean age of onset of this disease at 52.5 years. The male to female ratio ranges from 1.1:1 to 1.9:1. Mean survival time ranges from 5.5 to 9.5 years.
Treatment
The parkinsonian features in multiple system atrophy respond poorly or, at best, have modest response to dopaminergic agents. Anti-cholinergic agents and amantadine sometimes give mild benefit. The cerebellar signs in multiple system atrophy do not respond to any medical treatment. For postural hypotension, a high salt diet, head up-tilt of the bed at night, and elastic support stockings or tights could be used. Other agents that help postural hypotension include ephedrine fludrocortisone and octreotide. Urinary bladder dysfunction can be helped with oxybutynin, as well as intermittent catheterization. Some patients have respiratory failure such as respiratory stridor, which may require tracheostomy (a tube inserted in the wind-pipe to help a person breath) if indicated. Some patients have dysphagia, which may require gastrostomy (a tube inserted in the stomach through which nutrition is given). In general, the medical treatment of multiple system atrophy is disappointing. Physical therapy, occupational therapy, speech therapy, and other measures for safety are of paramount importance.
Sultan Darvesh
See also Brain; Dementia; Demetia with Lewy Bodies; Fainting; Parkinsonism.
BIBLIOGRAPHY
Adams, R. D., Van Bogaert, L.; and Vander Eecken, H. "Striato-nigral Degeneration." Journal of Neuropathology and Experimental Neurology 23 (1964): 584–608.
DÉjÉine, J., and Thomas, A. A. "L'atrophie olivo-ponto-cérébelleuse." Nouveau Inconog. Salpetriere 13 (1900): 330–370.
Graham, J. G., and Oppenheimer, D. R. "Orthostatic Hypotension and Nicotine Sensitivity in a Case of Multiple System Atrophy." Journal of Neurology, Neurosurgery and Psychiatry 32 (1969): 28–34.
Nakazato, Y.; Yamazaki, H.; Hirato, J.; Ishida, Y.; and YAMAGUCHI, H. "Oligodendroglial Microtubular Tangles in Olivopontocerebellar Atrophy." Journal of Neuropathology and Experimental Neurology 49 (1990): 521–530.
Quinn, N. P., and Wenning, G. K. "Multiple System Atrophy." Advances in Neurology 69 (1996): 413–419.
Shy, G. M., and Drager, G. A. "A Neurologic Syndrome Associated with Orthostatic Hypotension." Archives of Neurology 2 (1960): 511–527.
Wenning, G. K.; Ben Shiomo, Y.; Magalhaes, M.; Daniel, S. E.; and Quinn, N. P. "Clinical Features and Natural History of Multiple System Atrophy: An Analysis of 100 Cases." Brain 117 (1994): 835–845.
Multiple System Atrophy
Multiple system atrophy
Definition
Multiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, cerebellar dysfunction, and autonomic disturbances.
Description
MSA causes a wide range of symptoms, in keeping with its name of "multiple system" atrophy. Parkinsonian symptoms include tremor, rigidity and slowed movements; cerebellar symptoms include incoordination and unsteady gait; and autonomic symptoms include orthostatic hypotension (drop in blood pressure upon standing) and urinary incontinence. Because of this wide variety of symptoms, it was originally thought of as three distinct diseases: striatonigral degeneration (parkinsonian symptoms), olivopontocerebellar atrophy (cerebellar symptoms) and Shy-Drager syndrome (autonomic symptoms). Further study showed the overlap among these conditions was best explained by considering them as a single disease with symptoms clustered into three groups. Historically, confusion about the disease was made even worse because olivopontocerebellar atrophy is also the name of an unrelated genetically inherited disease. It is hoped that widespread use of the name MSA will clear up some of this confusion.
Demographics
Because MSA is often misdiagnosed, figures on its prevalence are not known with certainty. It is estimated there are between 25,000 and 100,000 people in the United States with MSA. Onset is usually in the early fifties, and men are slightly more likely to be affected than women.
Causes and symptoms
The cause or causes of MSA are unknown. No genes have been found for MSA. Some evidence indicates that toxins may be responsible, but no specific agents have been identified. The brains of MSA patients reveal that cells called glia undergo characteristic changes. Glia are supportive cells for neurons, brain cells that conduct electrical signals. In MSA, glia develop tangles of proteins within them, called glial cytoplasmic inclusions. It is not known whether these actually cause MSA, or are caused by some other problem that is the real culprit.
The symptoms of MSA fall into three separate areasparkinsonism, cerebellar symptoms, and autonomic disturbances. The distribution and severity of individual symptoms varies among patients. MSA is a progressive disease, and symptoms worsen over time.
Parkinsonism is the initial symptom in almost half of all patients. The classic symptoms of Parkinson's disease (PD )—tremor, stiffness or rigidity, and slowed move-ments—are seen in MSA, although tremor is not as common, and is jerkier than the tremor of PD.
Cerebellar symptoms are the initial feature in very few MSA patients, but occur in about half of patients at some point during the disease. The cerebellum is an important center for coordination, and degeneration of the cerebellum in MSA leads to loss of balance, incoordination in the limbs, and loss of smooth eye movements. A person with cerebellar dysfunction in MSA typically walks with a wide stance to improve stability, and may lose the hand-eye coordination that makes so many simple activities possible.
Autonomic symptoms refer to those involving the autonomic nervous system. The autonomic nervous system controls a variety of "automatic" body functions, including blood pressure, heart rate, sweating, and bladder function. Autonomic symptoms are the initial complaint in half or more of all MSA patients. The most common initial problem is urinary dysfunction in women, and erectile dysfunction in men. Urinary dysfunction may be incontinence, or inability to void the bladder. Other autonomic symptoms include lack of sweating, constipation, and fecal incontinence.
Orthostatic hypotension is a common autonomic symptom. It refers to a significant drop in blood pressure shortly after standing. It can cause dizziness , lightheadedness, fainting , weakness, fatigue , yawning, slurred speech, headache , neck ache, cognitive impairment, and blurred vision.
Other symptoms may also occur in MSA. These may include:
- vocal cord paralysis, leading to hoarseness
- swallowing difficulty
- sleep apnea
- spasticity
- myoclonus
- Raynaud's phenomenon (cold extremities)
Diagnosis
The diagnosis of MSA is difficult, because it is easily mistaken in its earlier stages for Parkinson's disease, which is much more common. Autonomic disturbance also occurs in PD, but is much more pronounced in MSA. MSA is the more likely diagnostic choice when disease progression is rapid, and when the patient responds mildly or poorly to levodopa, the mainstay of PD treatment. Some centers use electromyography of the anal sphincter (the muscles surrounding the anus) in order to confirm the diagnosis of MSA. Abnormal results indicate MSA rather than PD, although this method is not universally recognized as valid.
Neuroimaging may be used to rule out other causes of similar symptoms, such as lesions in the brain or normal pressure hydrocephalus .
Treatment team
The treatment team includes the neurologist , possibly a movement disorders specialist, a urologist, and a speech/language pathologist.
Treatment
There are no treatments that halt or slow the degeneration of brain cells that causes MSA. Treatment is aimed at relieving symptoms.
Treatment of parkinsonian symptoms is attempted with standard PD drugs, namely levodopa and the dopamine agonists. Unfortunately, these are rarely as effective in MSA as they are in PD, although about one-third of patients have at least a moderate response. In the best case, treatment relieves stiffness, tremor and slowed movements, allowing increased activities of daily living.
Orthostatic hypotension is treated with medications to increase retention of fluids (fludrocortisone), compressive stockings to keep blood from pooling in the legs, increasing fluids, and increasing salt intake. Midodrine, a drug that helps maintain blood pressure is often prescribed.
A urologist may be needed to define the type of urinary dysfunction the patient has, and to manage treatment. A bedside commode or condom catheter may be helpful for urge incontinence, or inability to hold urine once the urge to urinate occurs. If incomplete voiding is the problem, intermittent catheterization may be needed. Detrusor hyperreflexia, in which the bladder muscle undergoes spasms, may be treated with drugs to reduce these spasms.
Male erectile dysfunction may be treated with sildenafil or other medications.
Anhidrosis, or lack of sweating, can be dangerous in an active patient, because of the risk of overheating. Awareness of the problem and avoidance of prolonged exercise are helpful.
Gait ataxia may require a mobility aid, such as a cane, walker, or eventually a wheelchair.
Speech and swallowing problems are dealt with by a speech/language pathologist, who may work with the patient to develop swallowing strategies, and instruct in the use of assistive communication devices. Sleep apnea may be treated with continuous positive airway pressure ventilation.
Clinical trials
Clinical trials for MSA are usually directed toward better diagnosis, or symptomatic treatment. Until researchers develop a better understanding of the causes of the disease, little progress can be expected in development of treatments to slow its progression.
Prognosis
The average survival after diagnosis is 9-10 years. Death usually occurs from pneumonia or suddenly from insufficient respiration, due to degeneration of the respiratory centers in the brain.
Special concerns
Resources
PERIODICALS
Wenning, G. K., et al. "Multiple System Atrophy." Lancet Neurology 3 (2004): 93-103.
WEBSITES
Shy-Drager Syndrome/Multiple System Atrophy Support Group. <www.shy-drager-syndrome.org>.
WE MOVE. <www.wemove.org>.
Richard Robinson