too many clinicians method pathology
means the solution,
the final answer to the problems in the
diagnosis of neuromuscular diseases.
Yet like all other methods
of examination,
his pathology of the muscle tissue has
its restrictions.
And it's just one of the many ways of reaching a
diagnosis.
Muscle tissue has only a limited range of
histological changes in reaction to disease.
But on the other hand,
this number is so large that it is
impossible to show you every way of
reaction.
Therefore,
I have chosen a few pathological changes that
illustrates very well the possibilities and
the restrictions of muscle pathology.
I shall demonstrate some special fibers like
target fibers,
rink fibers and ragged red fibers and
some special morphological features like the
formation of cuba integrates
cars,
roads and the focal loss of cross
variation.
On this slide.
You see the five main methods
of examination and neurovascular
diseases and I want to
put forward to you that the order
is completely arbitrary
and there is no one of
these methods that is more important
than the other.
But I will talk about pathology
and that will be history,
pathology,
enzyme,
history,
chemistry and when necessary.
I'll show you some slides of the
electron microscopic features.
The first slide shows you a
target fiber called by DR King Engel in
1961 target fiber because it looks
like a target and especially this guy.
Graham ST,
glamorous tye.
Graham ST staying at the
core of this target stains
bread.
Right?
Then you see the target fiber with
an enzyme,
histone chemical reaction oxidative enzyme.
And then you see that the center of the target
is not stained at all.
That is because there are no mitochondria in the
center of these targets.
Sometimes you will find many of these
targets like here in the ordinary paraffin slides
stained for or
hear the cry state section.
And then you see many of these targets.
But in some cases you
only find one or two of these targets.
And in all cases you can say when you see targets
that it is a
involvement of the lower motor
neuron.
You cannot say that when there is an
involvement of the lower motor your
neuron,
you always see targets.
But when you see them then you
are allowed to say that this must be a
disease where the lower motor
neuron is involved.
Another special
fiber is called the linked fiber.
This is a fost relay staining.
And then you see these rings and the cytoplasmic
masters like here you see you're running ever and
Maya Federal through the psych a pleasant.
And when you look upon these
fibers in longitudinal sections in
the tristate stained sections.
Then you see these psycho plastic masses and the rink
fibers and here for instance is a high
oxidative enzyme activity in
this cycle plastic mass,
rink fibers are called rink fibers
because it looks if they have a ring
around them.
But actually this is not a ring with a
spiral and there's an aberrant Maya Federal
running like a spiral along the
longitudinal axis of this fiber.
And of course it's not often that you
cut just in the plane of this
spiral.
And then you can actually see see the
spiral.
More often it happens that you cut through the
spiral and then you only see
part of these aberrant maya
fables.
When you cut a ring
fiber transfer sections,
then you of course don't see a close ring
because it is not a ring but a
spiral.
And you always find somewhere
a place where the spiral begins
or ends like seen here in this
transfer section of this particular muscle
fiber.
This is an E.
M.
Of a rink fiber.
And you can see the event Maya fables running
around this transfers
section of the main fiber
mass.
And here is a
example of linked fibers
and our and cytoplasmic masses in
10 autopsies.
Then on elderly,
normal people without any neuro muscular
diseases.
And you see here on the left side the blue
missiles and here the other missiles.
And these missiles have a lot of rink
fibers and psycho plastic masses.
And here on the left hand side there are
only a few missiles containing one or
several rink fibers.
The difference between the left and the
right group of missiles is
that here all the missiles have a tenderness
insurgent to bone.
And these missiles do not have any
tenderness insurgent to bone.
When you take a missile of a guinea
pig that normally does not
contain any rink fibers and you
make it a missile like in the normal human
just by doing a sonata me.
Then after half a year you will see these
ringed fibers develop and then you just
cut the missile fiber,
the missile on a as a whole.
Then again after half a year,
you see these rink fibers and cytoplasmic
masses appear.
So if you see in
a biopsy,
ring fibers.
And then I think pathology
is very low in rank
because actually ring fibers are
not pathological in every case because
normal people can have them.
And furthermore you can say that rink
fibers will develop in any
case when the normal continuity of the
missile fibers has been disrupted by
pathological process.
For instance replacement of the missile
by fed tissue.
Often people say that in
my atomic dystrophy you see many
ring fibers and that happens to be true.
But on the other hand,
my atomic dystrophy is one of the few neuro
muscular diseases that you can easily
recognize just by physical examination
and so you don't need in this particular
disease.
A biopsy to confirm
your diagnosis.
Another kind of rings scene
are these Granules around some of these
muscle fibers,
sip psychological collections
of Granules and in longitudinal
sections,
you will see that again
there are many of these Granules
present in the cycle Emel region.
Sometimes the whole of the
fiber of part of the fiber is
involved.
And all these Granules happen to be a
mitochondria.
When you do a tri gram stain modified,
try gram stain on christ eight
sections.
Then you see these collections of
mitochondria are stained red and
therefore they are called ragged red
fibers.
Right.
Red fibers have a very
high oxidative enzyme activity because
they consist of a
collection and increase of uh
mitochondria.
And this is a higher magnification
showing you the
particular pattern that has gone.
And all of the fibers
are have a very high
oxidative enzyme activity.
Because most of the fibers a
fiber has been replaced by
mitochondria.
This is an example of a paraffin slide.
And here again you see this tri gram staining
technique with this venue.
Als And when you see a similar fiber like this
in crime state section then of course all
of the fiber has a very
very high oxidative enzyme
activity.
Uh ultra structural.
You see there is a collection of
of mitochondria abnormal in
shape and often the cursed
are thickened.
And here again you see the very
bizarre formation and
shape of this mitochondria.
Most of the times in these particular
collections the mitochondria are
enlarged as well.
And often you will find these
particular uh so called para
crystalline inclusions or parking lot
inclusions.
And these again are by no means
very specific for this
group of diseases.
Uh sometimes these diseases
or myopathy czar called mitochondrial myopathy.
But the only thing they have in common is a
increase of collections of
mitochondria and you can have all
kinds of muscular involvement,
all kinds of other manage stations.
And so when you see these
mitochondria,
you cannot say this is a mitochondrial disease.
You only say that this is a
myopathy with abnormal mitochondria.
And then there are many possibilities left for a
correct diagnosis in these cases.
Another red
collection in the diagram stain
is the formation of so called tubular
agra grades.
And here you see this
these two braga grades are only
found in the dark fibers.
Type two fibers.
This is an A.
T.
P.
S.
A.
T.
P.
A staining.
And here again you
see that in the light fibers there
are there are collections
of tubular Agra greats with a very high
oxidative enzyme activity.
That is to say when you use any D.
H.
Oxydol reductase
methods on the other hand,
the typical so called mitochondrial
enzyme like 16
hydrogen has no
increase of his
activity in this particular fibers.
These are the type to fibers and here are the tubular
aggregate but they have no increase
of their this particular enzyme
activity.
And the same is true for this particular enzyme.
Here are dark fibers are type two fibers and again
no activity is seen in these
regions.
So apparently these are not
mitochondria
and there are two bills
like seen here at the ultra structural level
and therefore they are called tubular agra
grids.
Uh people still
think that these are derived from
mitochondria.
but other people think that they
consist of a market proliferation of
the psycho plastic ridiculous.
So when we see the features
of these tubular aggregates,
you can say that with the
mitochondrial collections sub cycle
um a collection of mitochondria they have in common
that they stay in bright red with the modified tri
gram stain.
And both of them have no activity
of minors in a TPS.
But the big difference is the tuba aggregates
are only situated in Type two fibers
while the mitochondrial
accumulations are often seen in
Type one fibers.
Although they can be found also
in Type two fibers.
And then of course mitochondrial
AGRA grades have a high
activity for these enzymes as
well.
Now I come to seven patients we saw
recently,
Men and women and you can see
that this is a disease with a very
long duration 25 years or
13 years.
And these people suffered from a
very slowly progressive a
proximal myopathy limb girdle type of
myopathy without any special
features.
These little white stars means there is a
slight elevation of the CPK level in the
serum.
But you see that this man,
for instance has the disease for 25 years.
And this man has also for 25
years but his CPK is
normal and this is just slightly elevated.
So we had the hope that we could
diagnose these cases by means of
missile biopsy and I will now show you the
missile biopsy of a few of these
cases.
And first of all you see here and transfer
section of a perfect slide
state stained with H.
And E.
And there's nothing much to
see.
There's a normal diameter of most of the
fibers.
There's no increase of fat tissue or
increase of connective tissue.
There are no cellular infiltrates.
But yet you can see in this fiber
very tiny little factual.
And you see here in this fiber three
factual as well.
Another biopsy of another patient shows
more of these vegetables.
For instance here in many of the fibers
are very large
Victuals and some of the fibers.
Another possibility.
This is a crisis state section state with H.
And T.
Is that most of the fibers are normal and
just one single fiber is involved.
And then you see these very very many
of these very tiny
vegetables.
Uh The solution is that
when you see a child with the same
uh kind of disease
then it's called uh
gino sis.
This is pompous disease.
And of course then there are no difficulties
and recognizes in recognizing
these particular cases.
And when you do a P.
A.
S.
Staining then of course you see the
accumulation of P.
A.
S.
Positive material.
And all these patients
showed seven patients were suffering
from type two sm smell test
deficiency.
Type two uh
glycogen storage disease.
And in Children this is called pompous
disease.
You see that there are eight types
and in many of these types.
The missiles are involved as well.
Andersons disease is very rare
and forceful frank
tokens deficiency also
is very rare in the built patients.
In most of these
cases you can
diagnose the enzyme deficiency
by biochemical as say.
And as a matter of fact,
the seven patients I have shown the
muscle tissue and leukocyte
uh did not contain
the asset melters
enzyme.
So in this particular group of
diseases,
glycogen storage diseases or glycogen Gnosis,
biochemistry is the main thing
for a correct diagnosis.
Pathology may give you a
clue when you see as is in
the case in melted deficiency.
When you see these Victuals.
And by the way,
these Victuals show a very high
activity of a license thermal
enzyme that is
acid phosphate.
Sometimes just the
histone pathology may give you the
correct diagnosis.
For instance,
as seen here in central
core disease,
the central cost and blue
but it is very difficult to recognize them in an
H and E stained section.
And this is a long funeral section and again,
you see easily these blue stained
cause and it's very difficult to recognize them
here in the H and E.
This happened to be our first case of
central core disease.
And again you see the cars
running along the longitudinal
section of these particular
fibers and all the cores are staying
blue
when you do cry state sections in these cases
you see that the courts are found only in
type one fibers.
The light fibers here in the Maya february https
staying are type one.
And here the dark fibers are of type one.
So you see many
uh type one fibers
containing these costs
and this is another patient.
And then you see that almost all type one
fibers contain one or several
cost and none of the type
two fibers show any course at all.
This is a higher magnification of a core
region showing you that this region
is devoid of any enzyme activity and that's
because there are no mitochondria
mitochondria in this particular area of
the muscle fiber.
And this is a transfer section showing
again that the oxidative enzyme
activity is present at the
peripheral rim with this core
region is almost devoid of enzyme
activity.
Another morphological feature
readily seen is the
formation of rods and this is a case of
congenital name allene myopathy.
And here is a transfer
section of another case.
And then it's very difficult to recognize the
fiber not containing any roads.
Most of the fibers contained rods
and as you will see here,
most of the roads have a sub
cycle level position.
But of course sometimes you see them in the
middle of the fibers as well.
And this is in direct microscopic
picture showing you the sub cycle
collections of these rods
and the next one shows
you that also in the interior
of the fiber rods are
present.
And as you know,
these rods derived from the C.
Disk as seen here,
another feature morphological feature of
mammalian myopathy is a type
one fiber predominance or as
you can call it also type two fiber
positive.
And this is an
example of a patient suffering from
mammalian myopathy and it's obvious
that this is an auto Zamel dominantly
inherited disease.
However,
this is another case of typical mammalian
myopathy and this
patient has a healthy mother and
unhealthy father.
So
uh you can say that is
a AutoZone dominantly inherited
disease called family myopathy.
And maybe there is another disease
that is a recessive inherited
kind of Nummelin myopathy.
So far there are seven
publications of
authors who have examined in cases
of normally myopathy,
the mother and the father as well.
And then you see that in four of these
cases the murder was suffering from muscular
weakness and in two of these cases
the mother was showing rods in her
muscle biopsy as well.
So apparently these are examples
of autism,
all dominantly inherited kind of
type of Nummelin myopathy.
But on the other hand,
there are many patients with completely
healthy fathers and mothers
and non no
roads in the biopsies
dr arts.
In our laboratory had the opportunity to examine
six patients suffering from
lean myopathy.
And in all these patients the father and the murders
were examined and then you see there's only one murder
showing muscular weakness and in all the other
cases no muscular weakness was was
present.
Yet in two parents,
two pair of parents.
There were rots in there
In the biopsy and this was
confirmed in three cases by electron
microscopy.
So coming back to that particular
patient patient I showed you
this patient is suffering from muscular weakness
and he is showing rods in his biopsy.
His pants are completely normal,
but in the biopsy they
also show rods.
And that means that this is a auto so more
recessive mode of transmission
when you see rods in the missile biopsy.
That by no means means that you
have to do with a rod
myopathy.
Because ever since a 50
in 1965 found rods
so called secondary roads in central core
disease.
Almost every year year there has been
somebody who found rods
in all these kinds of different
missile diseases.
And this is an example of
central Curtis's.
This is the core showing
like microscopically Rod's collection of
sub cycle lemon rods and this is the E.
M.
Of the same patient.
Another kind of morphological
uh change in the
missile fiber is the so called focal loss
of cross stations.
This is in trans first section.
And first of all,
you see the white variation of the
diameter of the missile fibers.
And moreover,
you see the increase of internal nuclei
trans in longitudinal sections
stained with P.
T.
H.
You will see that all of a sudden there is a loss
of cross striations in these particular parts of the
muscle fibers.
And moreover,
you will see see that in these particular
regions there are many
nuclei,
this particular nuclear line.
And again this is showing you a case
of so called focal loss of cross
creation.
And here again you can see there
are no cross striations in these particular
areas.
And again there is an increase of particular
nuclei and you can see that the
transition between normal and
abnormal is very sharp.
And here again is a chris state
section stained for oxford enzyme
activity.
And in these zones where
the loss of cross striations is
present,
there is no activity.
And that is because there are no
mitochondria as shown here in the
E.
M.
Picture.
This is the normal part of the missile showing
many mitochondria and all of a sudden there's a
very sharp transitional zone
between normal and abnormal.
This is the focal loss of cross creations
zone and there is a streaming of the Z.
Discs and there is no mitochondria.
And again like in other types of
so called congenital myopathy.
You will see there is a type two
positively or Type one predominance
more often in these cases of
uh focal loss of cross
striations,
there is not only a Type one predominance
but the type one fibers are
too small.
So there is a type one fiber hypertrophy
according to Brooke and angle the
normal diameter of this boy
whose age is six years
is 30 to 40
microns.
And you can see that his
mean diameter is much
smaller.
So in focal loss of cross
striations.
Central core disease.
Normally myopathy
Pathology is # one.
It's very important to know
that when you see things
like for instance a core
or a rod,
then you cannot diagnose this case
without a muscle biopsy.
On the other hand,
I think it's you're not justified to
say that a disease
is rot myopathy
because you see rods and I will give
you an example of this
particular difficulty we
can encounter.
This is a pedigree showing you a
boy suffering from a congenital
progressive myopathy.
He has five completely
normal healthy sisters and his
mother and his father both are very,
very healthy.
Now I show you first of all the
muscle tissue of this boy.
And first of all you see that there is again
a Type one predominance.
All these type all these fibers are of
type one.
And then you see that he
also has focal loss of cross
striations here and there are no
cross striations scene.
And moreover,
he has the typical collections of
these particular nuclei.
But in another part of his
biopsy we found the
collection of rods and this by the
way was confirmed by electron
microscopy.
Then we did a biopsy in the deltoid
missile of his completely normal father
without any signs or symptoms of
neuro muscular disease.
And then you see this father
also shows a predominance
of Type one fibers or a positive of type
two fibers.
And moreover,
These fibers,
type two fibers angular dated and
small.
And this healthy man also
showed collections of rods
in the cryo states section stand
for with a
modified try growing state.
Now I will show you The missile
biopsy of the murder and she has a
beautiful normal mosaic
pattern of type one and type two
fibers.
But this lady again
showed collections of roads
and the modified tri
gram stain.
So when we look at the
pathology in these cases,
you can say that these
people had rods
and their son had rods and focal
loss of cross striations.
And you compare
pathology with muscular
weakness.
Then you can say this
apparently is an auto so more recessive
disease.
But that's all you can say.
You are not allowed to say that this boy is suffering from
Hamelin myopathy with some
focal loss of crustaceans.
And you are not allowed to say that he is suffering from
focal loss of crustaceans with the formation of
some rods.
The name of this disease as yet
is not known.
And the same problem we had with the
other family in which the
disease apparently was autism,
A dominantly dominant inherited.
And here you see the grand matter,
Her son and a little girl 8
7.
When we saw her,
I first will show you a few slides
of the grand murder.
And here again you see the
cycle sub cycle Imo collections of
roads.
Beautiful roads are seen here and there is an
increase of vesicular nuclei.
And another picture of her
biopsy shows again the sub cycle M.
O.
Collections of these rods
everywhere.
And I must say that seven years
ago I diagnosed this case as a
case of normal in myopathy.
Now I will show you a picture
of a vessel biopsy of her sin,
the father of this little girl.
And then you see that this
man shows focal
loss of cross striations.
Typical picture of focal loss of cross striations.
And here is in a state section
showing you the loss of enzyme
activity in these regions because I know
mitochondria and this
is again a very sharp
demarcation between normal and
abnormal.
But moreover,
you see a collection of rods here
and a collection of rods there and this again
was confirmed by
electron microscopic investigations.
And now I'll show you the biopsy of
this seven years old girl.
And she again
showed a typical picture morphological
picture of focal loss of cross station.
Here is a beautiful
zone.
All the cross stations are
lost.
And here is the
collection of physical er
nuclei.
And again this
lady showed
a collection of rods seen at the ultra
structure level.
So when we compare
pathology with clinical
features,
then you see that the grandmother
had normally myopathy
because he had so many name a leans.
But after re examination of
her biopsy I found two fibers,
just two fibers showing focal loss of cross
station.
And this man showed both of them.
And this little girl showed
mainly focal loss of crustaceans with a
few uh rods
seen at the ultra structure level.
And when we compare these two
muscular weakness and the pathology again,
the only thing you can say is that there is
a lot a zonal dominantly
inherited myopathy.
And you cannot say that
this girl is suffering from mammalian myopathy
with rods with
uh focal loss of crustacean or her
grandmother from focal loss of crustaceans with
rods.
Of course all these people are suffering
from the same disease.
And this last picture gives you
a symbolic
impression of what I like to say.
This is a painting
of the well known dutch artist Asher
for this reason for this occasion stained with
a and then you
see that there are people who have
caused in their biopsy
and there are people who have focal loss and there are
people with formation of roads.
But in some biopsies you can
find cause and roads or you can
find focal loss and roads.
And so far,
I've never came across a biopsy in
which you see cause and focal loss together.
So I hope that I have given
you at least an impression of some of the
pathological reactions of muscle
tissue.
In conclusion we can say that muscle
pathology can be the answer too many
questions and in some cases may even be
the very last answer.
MR pathology often shows a lot of
non specific reactions and in these
cases gives no answer at all.
Mr pathology may be dangerous
because it can tempt people to name a
disease after only one pathological
feature seen under the microscope.
Both all,
however,
we must be aware that MR pathology is
just one of the many ways that can lead to
a correct diagnosis.
Thank you.