RESEARCH REPORTS – Parkinson Report * Spring 1998

MULTIPLE SYSTEM ATROPHY

By members of the National Parkinson Foundation Center of Excellence at Vanderbilt University, including David A. Robertson, Director, Nathan S. Blaser Shy-Drager Research Laboratories; Thomas L. Davis, Director, Movement Disorder Clinic; and Ariel Y. Deutch, Director, NPF Center of Excellence.

Neurodegenerative Disorders

Although the cause of idiopathic Parkinson’s disease is unknown, Parkinson’s disease is probably the best characterized of the neurodegenerative disorders. The loss of dopamine in the striatum is the major contributor to the disorder. However, there are several other neurodegenerative disorders involving several different systems in the brain, in which striatal dopamine loss is also found.

Multiple System Atrophy

Among these other neurodegenerative disorders is multiple system atrophy (MSA), in which degeneration in diverse brain regions leads to problems in the control of movement, balance, blood pressure, and sexual and urinary tract function. MSA is often accompanied by some striatal dopamine loss and in certain patients typical Parkinsonian symptoms are either the first noted or the most prominent.

A number of areas of the brain are involved by MSA. This has led to different varieties of MSA receiving different names, depending on which area of the brain has predominant involvement. When MSA begins with imbalance, lack of coordination, and difficulties in speaking (dysarthria), it is often called olivopontocerebellar atrophy; as the name suggests, this form of MSA is marked by degeneration in the cerebellum, a structure involved in balance and learned motor tasks. When a patient initially has rigidity (stiffness) and slowness in initiating movements (bradykinesia) that is out of proportion to tremor, this MSA form has been called striatonigral degeneration, involving communication between nerve cells in the striatum and midbrain. In patients in whom changes in autonomic function dominates the initial presentation, particularly changes in blood pressure regulation, the MSA form is often called Shy-Drager syndrome.

We can expect research advances to culminate in a better understanding of and treatment for MSA and Parkinson’s disease over the next decade.

Diagnosing Multiple System Atrophy

Between 25,000 and 100,000 Americans have Multiple System Atrophy. However, many will not receive the correct diagnosis during their lifetime. This is due to the difficulty in differentiating MSA from other disorders (including relatively common degenerative disorders such as Parkinson’s disease and more rare ones such as pure autonomic failure). MSA usually occurs after age 50, which a slightly higher incidence in males. Patients usually have autonomic nervous system dysfunction first. Genitourinary dysfunction (difficulty with urination) is the most frequent initial complaint in women, while impotence is the most frequent initial complaint in men. Orthostatic hypotension (a large drop in blood pressure upon standing) is common and may cause dizziness, dimming of vision, head or neck pain, yawning, temporary confusion, slurred speech, and if the hypotension is severe, the patient may “faint” upon arising from a recumbent position. In spite of low blood pressure while standing, it is common for MSA patients to have high blood pressure when lying down. A fall in blood pressure following meals or in hot weather or following infection is quite common.

When MSA begins with non-autonomic features, imbalance is the most common feature. This difficulty in maintaining balance may be due to either cerebellar or Parkinsonian abnormalities. Some patients complain of stiffness, clumsiness, or a change in handwriting at the onset of MSA. The concurrent involvement in MSA of multiple brain systems subserving movement, including the striatum, cerebellum, and cortex, leads to the movement disorder as often being the most profound disability. Hoarseness or even vocal paralysis are relatively common, as are sleep disturbances, including snoring and sleep apnea. The ability to swallow foods and liquids may be impaired.

The initial diagnosis of MSA is usually made by carefully interviewing the patient and performing a physical examination. However, more testing is often needed to confirm the diagnosis. Among the tests that are helpful in determining the presence of MSA are several types of brain imaging including computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). Pharmacological challenge tests (administering certain drugs in the presence of various types of movements of the patient) may also be of help. In those patients with typical Parkinsonian signs, in incomplete and relatively poor response to dopamine replacement therapy (such as I-dopa [Sinemet]) may be a clue that MSA is present.

A Defining Feature of MSA

The characteristic involvement of multiple brain systems is a defining feature of MSA, and one that an autopsy confirms the diagnosis. Recently, several groups have reported the presence of unusual inclusions in certain types of brain cells. These glial cytoplasmic inclusions are, as the name indicates, typically found in glial cells, which are the structural and metabolic support elements of the brain but are not neurons (nerve cells). Glial cells are central to maintaining the correct balance of ions in the brain, without which neurons cannot survive. Moreover, glial cells express certain proteins that accumulate and thereby limit extracellular excitatory amino acids that can be toxic to neurons. These functions of glial cells, coupled with the presence of glial cytoplasmic inclusions in MSA but not Parkinson’s disease, have sparked considerable research interest. It is noteworthy that a different type of intracellular inclusion in nerve cells, the Lewy body, is present in Parkinson’s disease by not MSA.

In MSA, there is loss of function in the two divisions of the peripheral nervous system: the sympathetic and parasympathetic nervous systems. Although the autonomic nerves themselves are largely intact, the brain loses its capacity to properly engage them in control the autonomic function. Consistent with the involvement of many brain regions in MSA, the concentrations of many neurotransmitters in the brain are reduced in MSA.

No Known Cause of MSA

As with Parkinson’s disease, the cause of MSA remains unknown. Antibodies in the spinal fluid of patients with MSA have been shown to react with a specific area in an experimental animal brain, raising the possibility that MSA may be related to an abnormality of the immune system. It is also possible that MSA is due to abnormal folding of some unknown protein. At this time, however, these observations require independent confirmation in large groups of patients, and the relationship of such changes to specific symptoms in MSA remains unclear. What is clear is that there is a compelling need for research into the causes, and hence treatment and cure, of MSA and Parkinson’s disease.

MSA is a rare and sporadic disorder and available evidence does not support a hereditary component to the disorder. Among more than 400 patients evaluated at Vanderbilt University Medical Center’s Autonomic Dysfunction Center during the past 20 years, not one had a family member with MSA, although a number of them had family members with Parkinson’s or Alzheimer’s disease. While it is possible that a few of these family members diagnosed with Parkinson’s or Alzheimer’s disease might have actually had MSA, available data strongly suggests that MSA is not inherited. In Parkinson’s disease that is a similar but not identical situation, with hereditary forms of the disease representing only a small minority of the patients; even in these patients, the disease process differs somewhat from idiopathic Parkinson’s disease. There is no evidence that MSA is contagious; we have never observed people in the same house who developed the disease.

Given the relative rareness of MSA and the infrequent misdiagnosis of the disorder, it is not surprising that there is a paucity of careful epidemiological investigations of MSA that allow one to identify predisposing environmental factors. Although one report raised the possibility of a small effect of exposure to environmental toxins and another report suggested a slight correlation with prior head injury, these claims have not yet been supported by other studies. In particular, MSA does not appear to be related to or caused by prior alcohol or drug abuse, poor nutrition, or other disease process earlier in life.

Progression and Treatment of Multiple System Atrophy

MSA may progress rapidly. Patients survive an average of nine years following onset of illness; some patients live as much as twice this long. Current treatment of MSA is symptomatic. The most valuable agents is increase blood pressure are fludrocortisone and midodrine. In addition, most patients with MSA derive some benefit from typical antiparkinsonian medications such as levodopa (Sinemet), dopaminergic agonists (pergolide and bromocriptine), and anticholinergic drugs.

Summary

In summary, MSA is a severe neurodegenerative disorder of unknown cause. There is currently no cure for MSA, nor is there a therapy available that stops or slows the progression of the disease. At this time, treatment is aimed at treating problems as they arise, and thus requires careful monitoring of the patient by skilled and experienced clinician with expertise in MSA.

The lack of specific treatments to cure or slow the progression of MSA is disheartening to patients and their loved ones and caregivers. However, extensive research efforts aimed at advancing our understanding of MSA, Parkinson’s disease and other neurodegenerative disorders are in place, and we have enjoyed a period of very rapid advances in understanding of the pathophysiology of neurodenerative disorders. We can expect such advances to culminate in a better understanding and treatment for MSA and Parkinson’s disease over the next decade.