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[The National Institute of Neurological and  Communicative Disorders and Stroke]

[Presents]

[The Clinical Syndrome of A-L-S;  Mayo Clinic, Rochester, Minnesota; Donald W. Mulder, M.D.]

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[Donald W. Mulder, MD:] Thank you, Dr. Engel.

Ladies and gentlemen.

Dr. Engel has asked me to discuss with you this  afternoon

a clinical syndrome of amyotrophic lateral  sclerosis.

Perhaps in discussing this syndrome, I should  rather discuss

rather than knowledge by ignorance of the  syndrome.

Because, in truth, we know very little about this  disease

beside that which was described many year s ago.

The first description that we know of was out of  Aran.

And there really is very little that we can add to  that syndrome [F.A. Aran, 1850...projected slide]

as he described it.

If you read this initial description of his,

you note that there is a certain gestalt one gets of  hopelessness and despair.

And this surely is the attitude of the patient and  his relatives

as they… as they confront this disorder.

I'd like you to notice that he is talking about a  syndrome which involves the skeletal muscle.

It is a syndrome which begins usually  asymmetrically and may involve

any of the smo… skeletal musculature except for  the eye muscles or the cardiac muscle.

The syndrome is characterized by its relentless  progression.

If it begins about the throat, it’s called bulbar palsy.

If it begins in one of the extremities, it’s called  progressive muscular atrophy.

Almost always associated with the disorder, there is hyperreflexia

and other evidence of pyramidal tract signs.

But as a disorder progresses, these signs  disappear,

and we have left only evidence of a flaccid paralysis.

Perhaps this syndrome is most characterized by  that which is ab… absent in this syndrome.

For example, as I mentioned, the eye muscles  are not involved.

And the patient retains full motion of his… of his  eyes.

Except for that rare one or two percent of patients  who do develop a conjid… a conjugate paralysis

during their illness.

Similarly, these patients maintain their mental  faculties.

Thus, they remain alert, intelligent, and are well  aware what is happening to them

well into the terminal course of their disease.

In only about one percent of these patients is there evidence of a intellectual deterioration,

which sometimes seems associated with motor  systems disorder.

Similarly, there is little if any sensory involvement  unless one tests very carefully.

And then one can usually find some minimal  evidence of sensory loss

even though this clinically is not evident.

And finally, the patient's bladder and bowel  function remains intact to the end.

So that finally, we have this clinical picture  described by Aran of a patient who lies in bed.

Looking like a skeleton.

Imprisoned in its own body.

I first became involved and interested in this  syndrome many years ago

when I was assigned to… by the United States Navy to the island of Guam

during the Korean conflict.

It became apparent and had been known of  course for many years that  A-L-S

was very common on the island.

It was reported as early as the first medical  officer assigned to the island in 1900.

Subsequently, and particularly during World War Two,

many medical officers noted the unusual  frequency of the disorder on the island.

And reported this to their… and reported this to  the Surgeon General

and also published reports about this unusual  frequency.

At the time I visited the island,

this particular village.

The village of Umatac,

was one in which there were 200 adults.

At that time, we found seven patients who had the  disorder

living among the… living in that village of 700  people.

Thus the instance was almost 1000 times as high

as elsewhere in the world in this particular  village.

If one looks at the patients who had the disorder,

and this is one such patient who had the  disorder in the island.

You see that they fit Aran's description.

The patient is alert, he’s following the camera  with his eyes.

He lies there like a skeleton.

All of the skeletal muscles are involved,

and the clinical syndrome looked for all the world  as it did in the States.

Similarly, when we looked at the laboratory tests.

We found that those laboratory tests which were  available to us.

Including the neurophysiologic techniques.

Seemed to demonstrate that the illness was  similar to that seen in the United States.

The cause of this disorder was of course of great  concern to all who had seen

this unusual instance.

And many of us had the naive belief that anywhere where this disorder was so common,

it should be relatively easy to find the etiology of  the syndrome.

Unfortunately, as you know, that has not proven to  be so.

We first thought that perhaps this disorder was  hereditary,

and the natives seemed to agree with this… us  that this was possible.

When we searched, we found that there were  other neurologic diseases on the island.

For example, there were a great many patients

who had what we thought was a peculiar form of  Parkinsonism associated with dementia.

These patients look very similar to the patients

who we had seen during and immediately after  World War One.

Those patients with a postencephalitic form of  Parkinsonism.

They were patients who had marked rigidity.

Who had mental deterioration.

And really had very little if any tremor.

This too, was a disorder which went on to death.

As we watched these patients over the next few  years.

We were impressed that they did not seem to be  the same patients as those who had A-L-S,

but rather that they seemed to be a separate  group of patients

within the Guamanian… within the Guamanian  people, period.

As we went further,

we began investigating the possible, uh,  hereditary aspects of this disorder.

Can I have the next slide, please?

We were impressed as the natives had told us

that the disease had been present for many  decades.

For example, as you see on this sly… on this  slide,

which illustrates a page from the death records  of the, uh, of the Navy records

for the island of Guam.  You can see two  consecutive deaths.

One… both of them from the village of Umatac.

Both of them illustrating that the patients had  died of paralysis,

which is a Guamanian name for this disorder.

So it was apparent that this disorder had been  present on the island for decades,

and it did seem to us that it ran in families.

We had available the death records [of the]  United States Navy.

The birth, marriage, and death records of the  Catholic Church back to 1830.

And with these we were able to construct rather  extensive family records on these patients.

And we came up the records such as this.  Which  illustrate that in truth,

there were within a single family group many  individuals who had the disorder.

These individuals marked here.

But if you looked at this family pedigree carefully,

you’d see that there is no evidence of any of the  classic inheritance patterns.

Rather, you see that there is sort of a random  scatter.

As if this might only be coincidental.

That this very common disorder on the island of  Guam

occurred in this random fashion in a large family.

In truth, we knew how the disorder was inherited  in the United States

and elsewhere in the world.

And there the inheritance pattern is far different  than what we would see here.

This is the way it looks in the rest of the world.

Where the inherited pattern is five to ten percent  of all cases.

As you can see here,

the pattern is inherited as a dominant with really  very good penetrance.

This is a very famous family, the Weatherby  family, who published their own records in 1870.

So it did not seem that if A-L-S was inherited on  the island of Guam

that it was inherited in the pattern in which it was  inherited elsewhere in the world.

It is always seductive to speculate when you're in  another culture

and see people eating and living in a way that is  foreign to you,

to think that there may be some environmental  factor which accounts for their illness.

And it is true that on Guam there are things which  are different than they are in the United States.

People eat different foods.  They eat the cycad nut.  They eat cassava.

They chew betel, they drink tuba.

They do many things which are different than  what you and I do.

And we all speculated that this might possibly be  the etiology of the disorder.

Some toxic factor within their environment which  might account

for this unique high instance of A-L-S.

We fortunately had available to us a natural  laboratory.  In that, the Pacific Ocean

in that area is scattered with thousands of these  small islands

on which people all live in a similar kind of way.

They are different in one important respect,  however,

and that the Guamanian are a very… is a very  distinct

racial and cultural group from the remainder of the people

in the islands scattered through the Pacific.

But they do live in much the same fashion in the  other islands,

perhaps more primitively.

And they surely use more of the unusual foods  which may be toxic on the other islands.

So we investigated very carefully some of these  other islands.

This is the island of Rota.

We also examined many other islands.

Examining the large numbers of patients with  neurologic illness.

Discussing with the priests and with the local  magistrates on the islands.

Sick people that they knew of, and to our  amazement

we found that there were no patients who had A- L-S in the other islands

where they ate similar foods such as cycad and  such as cassava.

We did find, however, that wherever the  Guamanian people themselves had moved,

and they had moved to three other islands.

The island of Saipan, Rota, and Tinian.

That on these islands, there was an unusually  high instance of A-L-S.

So, at the conclusion of my military tour of duty,

I was really quite stymied.

We hadn't been able to demonstrate that the  disorder was hereditary,

nor had we been able to demonstrate

that the disorder was secondary to some toxic  factor

which might be present on these islands.

[...]

We did, however, come to conclusion that

one could at least classify the disorder in a  reasonable way.

One might classify it into the hereditary form

as seen in the States and elsewhere in the  world.

And a disorder which was inherited as a  dominant with good penetrance.

One could certainly… should, we felt separate  out the Guam form

for which we do not as yet know the etiology.

Then the classic or sporadic form,

and then finally we had listed also those  symptomatic forms

of amyotrophic lateral sclerosis,

for which we are able to demonstrate the etiology.

[...]

On my return to the States, obviously my interest  in this disorder continued.

And we thought that perhaps by making a  prospective study

of a hundred consecutive patients,

we might be able to turn up some leads

as to what allowed certain individuals to develop  disorder.

What allowed them to become vulnerable to  whatever the etiology was?

We conducted extensive studies on these  hundred consecutive patients.

And the result of them really were all negative.

As I followed these patients along, however, I  found to my amazement

that they did not seem to follow the characteristic  pattern I had been led to believe was true.

It is customarily said that patients with A-L-S die in two to three years.

And yet as we followed our patients, we found…  we found that approximately 20% of them

were still living at five years.

Ten percent of them were living at ten years.

And some were still living for 20 or… for nineteen  to 20 years.

It became apparent to me that there must be  something different

about this group of patients.

And we wondered whether or not we weren't  overlooking some other etiology for A-L-S

at this point in time.

For this reason, we conducted rather extensive studies on varied forms of symptomatic A-L-S.

In the hope that by doing so, we might find

in what way these patients who lived for a long period were different.

We actually were thinking or had thought that  perhaps this…

those patients with long duration had a different  clinical disease.

When one thinks about the syndromes which  may imitate A-L-S,

one finds they really are in two large groups.

One of them are the group of patients which is…  which is exemplified here.

Those who have inflammatory changes in the  spinal cord due to viruses, toxins,

immune disease,

a whole host of disorders.

And hyperinsulinism is only one of them.

Others, which are more common, include such syndromes as the Guillain-Barré syndrome.

Certain toxins such as a [?] Tri-O-cresyl  phosphate.

There are many such disorders,

and they can usually be readily differentiated.

Hyperreninism, a very rare syndrome.

But when hyperreninism does occur,

approximately 20% of the patients who have it

do develop a muscular atrophy,

which resembles amyotrophic lateral sclerosis.

The other important differential etiology is,

as you all know,

changes which cause compression of the spinal  roots or the spinal cord itself.

In the classic example of that of course are the hypertrophic changes

in the cervical spine.

Which are associated with compression of the  motor roots

There may be associated hypertrophic changes  in the lumbar spine,

causing changes in these roots.

Surprisingly enough,

this syndrome may present with a muscular atrophy

with almost no sensory signs.

A more exotic form of these same disorders

is seen here on a patient who has a rheumatoid spondylitis.

This syndrome in this particular patient presented as a… as a muscular atrophy

and might have been confused with A-L-S.

But the cause of the motor atrophy

was this hemorrhagic granulomatous pachymeningitis.

A similar pachymeningitis, such as that can occur with [?],

or more commonly now,

with with men… with meningeal carcinomatosis.

May also present as a muscular atrophy which could be confused with A-L-S.

It became apparent, however, as we studied these patients

that this did not explain those patients with A-L-S

who lived for a long period of time.

These were the differential diagnosis it is true of A-L-S,

but they were not the same as those patients

whose course persisted for so long a period of time.

In 1968, I had the opportunity of returning to the island of Guam.

While there, I again saw a number of patients with A-L-S,

and to my surprise,

three of the 52 I had originally seen in ’53 were still living.

One of them is this very nice man who,

as you can see again, fits Aran's description.

He's lying there, still in bed.

He's like a cadaver with his muscular atrophy.

His eyes however, are focused on us, and he's alert and intelligent

and remembered me after having… not having seen me for all those years.

Further, the clinical syndrome, in his instance,

had begun with bulbar pal… palsy, and he himself died the following year,

and that autopsy

seemed to be clearly that of a classic A-L-S as seen on Guam.

Thus, it became apparent that A-L-S also could live…

could last for a much longer period of time on Guam,

then we had ordinarily expected.  And more recently,

Reed, and his colleagues have published the duration of life

in their patients from the island of Guam.

And I think it's rather interesting to see

that this duration of life is almost identical

with that seen in our patients in States.

You can see that approximately at about 20% of them

live for at least five years or more.

Ten percent lived for ten years or more, and some of his patients

didn't die until… until they had had the illness for 20 years.

Thus it becomes apparent, I believe, that there are patients with A-L-S

in whom the clinical spectrum must be widened, and there must be a difference

in the vulnerability of the patient who have their disorder.

This concept, I believe,

becomes of particular importance in two ways.

First of all, perhaps, in what we tell patients.

Perhaps secondarily in that it gives us some hope that if the disease is so variable

that if we can understand why these variations occur,

we may be able to understand and begin to get a clue as to how to treat these disorders.

And finally, of course, it becomes of particular importance in attempting to interpret therapy.

Therapy in these disorders is really non-existent,

except for the ameliorate of techniques that you and I carry out as good physicians.

There are always, however, cures reported, and they just keep on going.

And there at the present time as always are four or five cures which are being touted.

I have come to the belief that these cures have occurred and are reported by

reputable physicians because they're not aware of this clinical characteristic

of the disorder that approximately ten percent of the patients live for these long periods of time.

This is a group of seventeen patients who I treated many years ago

with whole hog raw gastric mucosa.

I'm not sure that I could get that by any kind of a committee at the present time,

but at least this is what we did.

And you can see the clinical course of those patients

was almost identical to what has occurred in the hundred patients who I described to you.

Obviously, if you obtain these patients late in their course,

say that you only get patients after they've had the illness for three years.

Then you, of course, will get more of these with a long clinic course.

And I have seen a number of these patients, as many of you have,

I'm sure, who have gone from one center to another.  Having been in this clinical…

clinical course and who have been reported as cures with a variety of treatments.

Obviously, you and I know this isn't the only reason that therapy is reported as helpful.

The other reason is exemplified on this statement by a patient,

the great need of the patient and the physician to have therapy, to be helpful.

And this, of course, enters into all of our… into all of the treatment

that we give and is one of the reasons that there are so many therapies,

even for such a hopeless disease as A-L-S.

Perhaps then we might add:

is A-L-S really as hopeless as we've always believed?

It is almost unorthodox to talk about patients who may have gotten better.

I think all of us have a tendency to discard from

our consciousness patients who have shown improvement.

We intend not to include them in our classifications

or in our reported cases.

And yet I know that many neurologists

who have seen a great number of patients have seen such individuals.

This is one such patient.

I show him to you only to illustrate

that there are many things we don't really understand about this disorder,

yet, here is a physician who is in the neural sciences

who believed he had A-L-S.

He had progressive muscular atrophy

involving both an upper and  lower extremity with hyperreflexia.

He was seen by a neurologist and had an EMG,

and the tests were confirmatory.

He also had a spinal fluid and a myelogram.

He was sent to us at the Mayo Clinic,

and Dr. Frank Howard and Dr. Clark Millikan saw him

and agreed with the diagnosis

but felt that they should wait at least six months before coming to a final decision.

When the patient returned, to their surprise, he was much improved,

and the electomyogram was A-L-So improved.

This patient has continued to show improvement,

and at least for the last ten years

has been able to engage full time in his practice

and on careful examination,

we are unable to find any evidence of neurologic disorder.

I'm not sure whether this means that we ought to include

in the spectrum of A-L-S even patients who show improvement.

I think only time will tell

as we try to find the etiology of this disorder.

What do we know about the etiology? Really very little.

All of our leads have tom… come to nothing.

One of the most recent leads

was a suggestion that this disorder occurred in individuals

who had a particular kind of psychologic bent.

A particular kind of psychologic problem,

and that this in some way accounted for their disorder.

This was based on the M-M-P-I studies

and other psychologic studies on ten cases.

When we tried to reproduce this work, using 50 patients

and comparing it with our control series.

We’d found that our psychologic studies were normal

and that, as you can see.  The M-M-P-I in the males were almost identical,

and the M-M-P-Is in the female were identical.

Thus it would seem that at least in our patients,

there were no psychologic traits which characterized the patients with A-L-S.

Most of us, I think at this point in time, or many of us,

have the belief and it's really only a…  a hunch

that this disorder must be due… may well be due to

a slow virus which attacks certain vulnerable people.

Perhaps made vulnerable through some hereditary factor.

Having told you about… of my ignorance about this disorder.

And having shown you the limits of at least part of that ignorance.

I can only plead with you that at the present time,

what we need are people who can devise the proper question.

Because if we can put the proper question,

perhaps we can obtain the answer to this disorder.

Perhaps we will be able to find a treatment for these truly pathetic patients.

Thank you.

[The National Institute of Neurological and Communicative Disorders and Stroke]

[The Clinical Syndrome of A-L-S;  Mayo Clinic, Rochester, Minnesota; Donald W. Mulder, M.D.]

[This presentation sponsored by]

[The National Institutes of Health, Public Health Service]

[Department of Health Education and Welfare]

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