MSA ARTICLE: Autonomic Disorder Appears in Many Guises

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Multiple System Atrophy

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Autonomic Disorder Appears in Many Guises

By Francie

Don Summers knew something serious had happened to his wife, Gwen. They had

successfully worked a business together for 11 years, but she suddenly felt

too tired to do her job. Then she became incontinent. Although Gwen could

hold a pen, she couldn't remember what she should write. Her brain seemed to

have stopped sending her signals.

The Austin, Texas, couple shuffled from doctor to doctor, looking for the

cause of Gwen's strange symptoms. Five frustrating years later, they met

on, MD, a professor of medicine, pharmacology and neurology at

Vanderbilt University in Nashville, Tenn. He recognized Gwen's symptoms and

gave them the devastating diagnosis of multiple system atrophy (MSA), a

malfunction of the autonomic nervous system.

The Summers learned that Gwen's disease would gradually destroy her bodily

functions and claim her life within eight to 10 years. Gwen received the

diagnosis in 1992; she died of respiratory failure in 1997.

" The root of the illness is a dying off of brain cells that causes the

disease to progress, " Don Summers explained. " The brainstem does not send

the signals out over the nervous system. "

MSA is considered a rare disease, occurring in about five to 15 people in

100,000, usually between ages 50 and 70 years. However, physicians familiar

with the condition believe it's significantly underdiagnosed and often is

misdiagnosed as Parkinson's disease.

Striking Symptoms

Dr. on acknowledged that diagnosis is tricky because the disease

appears in many guises, some of which have little in common. Patients

present with multiple symptoms, including shortness of breath, strange sleep

disorders, fainting spells, fatigue and incontinence.

While Gwen Summers gradually lost her mobility and cognitive functions, a

55-year-old woman diagnosed by C. Gay, MD, of the Mayo Medical School

in Rochester, Minn., suffered from a breathing disorder and excessive

daytime somnolence. She snored loudly, thrashed in the bed with violent arm

and leg movements and emitted a strange squealing-type inspiratory sound

during REM sleep. This woman, also wheelchair-bound, was morbidly obese.

Like many MSA patients, she needed a trach.

" The patient actually presented with acute respiratory failure, " Dr. Gay

explained during a lecture on MSA at the 23rd Annual Meeting of the National

Association for Medical Direction of Respiratory Care held in Napa Valley,

Calif.

Another of Dr. Gay's patients, a 70-year-old man, had been diagnosed with

non-positional obstructive sleep apnea several years earlier and used CPAP

at night. He had some gag reflux, but his wife did not sound the alarm until

he developed the violent arm and leg movements and high-pitched snoring

sound during REM sleep.

Even though the disease takes its toll in different ways, a hallmark symptom

will pin down the disease every time, Dr. on notes.

" Check the supine and upright blood pressure, " he advises. If the examining

physician repeatedly finds a large discrepancy between the two readings that

are not attributable to other common causes, such as dehydration or drugs,

the patient almost certainly has autonomic dysfunction and possibly has MSA.

" The blood pressure of these patients is highly dependent on respiration, "

Dr. on explains. It is " dramatically raised by hypoventilation and

dramatically lowered by hyperventilation. " The autonomic impairment results

in blood pressure swings that may rise as much as 50 percent.

" It's very striking, " Dr. on says.

Misdiagnosis

To distinguish MSA patients from those who have Parkinson's disease, Dr.

on suggests additional testing for any who need wheelchairs, who fail

to respond to Parkinson's drugs, who have urinary/bladder problems, loud

respirations at night and any whose disease is progressing rapidly.

" These are things you might see in the clinic to tell a typical Parkinson's

patient has MSA, " he says.

The incidence of misdiagnosis in the United States isn't known, but a 1999

study published in Lancet provides estimates for Great Britain. A. Shrag and

colleagues1 screened the computerized records of 15 general practices in

London, identifying patients with diagnostic labels that suggested

Parkinson's disease. They assessed the patient (including interviews and

examinations) and concluded that incidence rate for MSA was 4.4 per 100,000.

An examination of the UK Parkinson's Disease Society Brain Bank showed that

of 100 patients who died with a diagnosis of Parkinson's disease, 5 percent

actually had MSA. From 1989 to 1994, approximately 9.9 percent of 303 brains

donated to the bank had MSA.

Defining MSA

A short definition of MSA, developed by the American Autonomic Society (AAS)

describes the condition as " a sporadic, progressive, adult onset disorder

characterized by autonomic dysfunction, Parkinsonism and ataxia (a failure

of muscular coordination) in any combination. " MSA symptoms follow three

paths, with certain symptoms being more dominant in each category:

Parkinsonism, marked by bradykinesia with rigidity or tremor or both.

Patients usually exhibit a poor or unsustained motor response to chronic

levodopa therapy. When Parkinsonian symptoms dominate, physicians often

refer to MSA as striatonigral degeneration.

Cerebellar or corticospinal signs. Sometimes referred to as sporadic

olivopontocerebellar atrophy, these symptoms often appear in combination

with Parkinsonian features.

Orthostatic hypotension, which includes impotence and urinary incontinence

or retention, usually preceding or within two years after the onset of the

motor symptoms.

Progressive autonomic failure was originally labeled as Shy-Drager's

Syndrome, for Milton Shy, MD, at the National Institutes of Health in

Bethesda, Md., and Glen Drager, MD, of Baylor College of Medicine in

Houston, who identified a common set of neurological symptoms associated

with autonomic failure in 1960.

Four years ago, Dr. on recalls that physicians associated with the

AAS met to decide on an appropriate term to describe the disease. MSA won

out. Included in the group was Britain's

Sir Roger Bannister, famous in athletic circles for breaking the four-minute

mile.

While Dr. on accepts the group decision, he admits he favored

Shy-Drager's Syndrome as the more suitable term.

" MSA sounds so awful, " he says. " It sounds like you are falling apart. "

Search for Mechanisms

Although respiratory symptoms such as shortness of breath are common among

MSA patients, Dr. on believes most cases of MSA are not diagnosed by

a pulmonologist. Patients don't always seek them out, starting perhaps with

a primary care practitioner and moving on to a cardiologist and a

neurologist. Dr. on estimates that about 50 percent of MSA patients

are under the care of a neurologist, about 30 percent see a cardiologist and

20 percent seek physicians representing a variety of other disciplines.

" The key is not the specialty but that the person knows about autonomic

problems, " he explains.

Dr. on developed an interest in MSA as a medical student when he met

a patient who had the disease.

" I thought this is something that really has to be solved, " he recalled.

" It's a devastating illness. "

Dr. on expected to find a cure for MSA within five years, but now, 35

years later, he realizes that was a naïve expectation. He and his colleagues

believe they are making some progress in terms of understanding the

mechanism of the disease. Writing last year in the NEJM,2 the group reported

" genetic or acquired deficits in the norepinephrine inactivation may

underlie hyperadrenergic states that lead to orthostatic intolerance, " such

as MSA

In a second NEJM article3 published Oct. 5, the group reported that plasma

norepinephrine concentration in the femoral vein was lower in patients with

postural tachycardia syndrome (a form of dysautonomia) than in normal

patients, prompting the Vanderbilt group to suggest the condition is linked

to partial sympathetic denervation, especially in the legs.

A group of physicians at the Mayo Clinic and McGill University in Montreal

shed more light on the syndrome when they tested serum from 157 patients

with various types of dysautonomia. Also writing in the NEJM,4 they reported

that these patients could be identified by seropositivity for antibodies

that bind to or block ganglionic acetylcholine receptors.

" The positive correlation between high levels of ganglionic-receptor

antibodies and the severity of autonomic dysfunction suggests that the

antibodies have a pathogenic role in these types of neuropathy, " the

investigators concluded.

Coming to Terms

While clinicians search for the mechanisms of the disease, patients and

their families flounder around, coming to terms with the depressing

prognosis their loved ones face. Summers serves as president of a support

group and fields up to 70 calls per week from desperate families. He often

has bad news for them.

" People call and say, 'I've got this disease. How can I treat it?' You

can't, " he says. " Dr. on helped us understand early on that we were

dealing with a terminal illness. Not all physicians make this clear. "

Summers knows families can gain strength from each other and helps organize

an annual conference for MSA patients. He likes to schedule the meeting,

which may draw a crowd of 36 patients and caregivers, at the same time and

city as the AAS annual meeting. This enables him to find physicians who will

volunteer to share their knowledge with patients. Travel is difficult for

many of the patients who need wheelchairs or walkers, so Summers looks for a

hotel that is close to an airport.

Summers understands the pain families face as they watch the deterioration

of someone they love. He says he watched his wife " fight so hard to make

some improvements in her life... never succeeding. "

He recognizes this determination in the MSA patients, their families and the

committed caregivers he meets.

" Every last one of them is a determined fighter, " he says. " I have never

seen such a collection of courageous people. "

References

Shrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive supranuclear

palsy and multiple system atrophy: A cross-sectional study. Lancet.

1999;354:1771-5.

JR, Flattem NL, Jordan J, G, Black BK, Biaggioni I, et al.

Orthostatic intolerance and tachycardia associated with

norepinephrine-transporter deficiency. NEJM. 2000;342:541-9.

G, Costa F, JR, on RM, Wathen M, Stein M, Biaggioni I,

et al. The neuropathic postural tachycardia syndrome. NEJM.

2000;343:1008-14.

Vernino S, Low PA, Fealey RD, JD, Farrugia G, Lennon VA.

Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic

neuropathies. NEJM. 2000;343:847-55.

Francie is senior editor of ADVANCE